(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT)
(19) World Intellectual Property
Organization
International Bureau
(43) International Publication Date
28 April 2005 (28.04.2005)
PCT
II
(10) International Publication Number
WO 2005/037285 Al
(51) International Patent Classification^: A61K 31/517,
31/4709, C07D 401/12, 401/14, A61P 43/00
(21) International Application Number:
PCT/US2004/0341 85
(22) International Filing Date: 15 October 2004 (15.10.2004)
(25) Filing Language:
(26) PubUcation Language:
English
English
(30) Priority Data:
60/511,851
16 October 2003 (16.10.2003) US
(71) Applicant (for all designated States except US)i CHI-
RON CORPORATION [US/US]; 4560 Horton Street,
Emeryville, CA 94608-2916 (US).
(72) Inventors; and
(75) Inventors/Applicants (for US only): RAMURTHY,
Savithri [IN/US]; 4560 Horton Street, Emeryville, CA
94608-2916 (US). RENHOWE, Paul, A. [US/US]; 4560
Horton Street, Emeryville, CA 94608-2916 (US). SUB-
RAMANIAN, Sharadha [IN/US]; 4560 Horton Street,
Emeryville, CA 94608-2916 (US).
(74) Agent: SHELTON, Dennis, K.; Christensen O'Connor
Johnson Kindness PLLC, Suite 2800, 1420 Fifth Avenue,
Seattle, WA 98101 (US).
(81) Designated States (unless otherwise indicated, for every
kind of national protection available): AE, AG, AL, AM,
AT, AU, AZ, BA, BB, BG, BR, BW, BY, BZ, CA, CH, CN,
CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, EI,
GB, GD, GE, GH, GM, HR, HU, ID, XL, IN, IS, JP, KE,
KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MA, MD,
MG, MK, MN, MW, MX, MZ, NA, Nl, NO, NZ, OM, PG,
PH, PL, PT, RO, RU, SC, SD, SE, SG, SK, SL, SY, TJ, TM,
TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, YU, ZA, ZM,
ZW.
(84) Designated States (unless otherwise indicated, for every
kind of regional protection available): ARIPO (BW, GH,
[ Continued on next page]
(54) Title: 2,6-DISUBSTITUTED QUINAZOLINES, QUINOXALINES, QUINOLINES AND ISOQUINOLINES AS
INHIBITORS OF RAF KINASE FOR TREATMENT OF CANCER
CD
(57) Abstract: New substituted quinazoline, quinoxaline, quinoline and iso-
quinolinc compounds of formulae (I) -(IV), compositions and methods of in-
hibition of Raf kinase activity in a human or animal subject are provided. The
new compounds compositions may be used either alone or in combination with
at least one additional agent for the treatment of a Raf kinase mediated disor-
der, such as cancer. The substituents are defined in the claims.
wo 2005/037285 Al IIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIIH^^^
GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM,
ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM),
European (AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, EI,
FR, GB, GR, HU, IE, IT, LU, MC, NL, PL, PT, RO, SE, SI,
SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ,
GW, ML, MR, NE, SN, TD, TG).
Published:
— with international search report
before the expiration of the time limit for amending the
claims and to be republished in the event of receipt of
amendments
For two-letter codes and other abbreviations, refer to the "Guid-
ance Notes on Codes and Abbreviations" appearing at the begin-
ning of each regular issue of the PCT Gazette.
wo 2005/037285
PCT/US2004/034185
2, 6-DISUBSTITUTED QUINAZOLINES , QUINOXALINES , QUINOLINES AND ISOQUINOLINES AS
INHIBITORS OF RAF KINASE FOR THE TREATMENT OF CANCER
FIELD OF THE INVENTION
The present invention relates to new substituted quinazoline, quinoxaline,
quinoline and isoquinoline compounds and pharmaceutically acceptable salts^ esters or
prodrugs thereof, compositions of the new compoiands together with pharmaceutically
acceptable carriers, and uses of the new compounds, either alone or in combination with
at least one additional therapeutic agent, in the prophylaxis or treatment of cancer.
BACKGROUND OF THE INVENTION
The Raf serine/threonine kinases are essential components of the Ras/Mitogen-
Activated Protein Kinase (MAPK) signaling module that controls a complex
transcriptional program in response to extemal cellular stimuli. Raf genes code for highlj?^
conserved serine-threonine-specific protein kinases which are known to bind to the ras
oncogene. They are part of a signal transduction pathway believed to consist of receptor
tyrosine kinases, p21 ras, Raf protein kinases, Mekl (ERK activator or MAPKK) kinases
and ERK (MAPK) kinases, which ultimately phosphorylate transcription factors. In this
pathway Raf kinases are activated by Ras and phosphorylate and activate two isoforms of
Mitogen-Activated Protein Kinase Kinase (called Mekl and Mek2), that are dual
specificity threonine/tyrosine kinases. Both Mek isoforms activate Mitogen Activated
Kinases 1 and 2 (MAPK, also called Extracellular Ligand Regulated Kinase 1 and 2 or
Erkl and Erk2). The MAPKs phosphorylate many substrates including transcription
factors and in so doing set up their transcriptional program. Raf kinase participation in
the Ras/MAPK pathway influences and regulates many cellular functions such as
proliferation, differentiation, survival, oncogenic transformation and apoptosis.
Both the essential role and the position of Raf in many signaling pathways have
been demonstrated from studies using deregirlated and dominant inhibitory Raf mutants
in mammalian cells as well as from studies employing biochemical and genetic
techniques model organisms. In many cases, the activation of Raf by receptors that
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Stimulate cellular tyrosine phosphorylation is dependent on the activity of Ras, indicating
that Ras ftmctions upstream of Raf. Upon activation, Raf-1 then phosphorylates and
activates Mekl, resulting in the propagation of the signal to downstream effectors, such
as MAPK (mitogen-activated protein kinase) (Crews et al. (1993) Cell 74:215). The Raf
5 serine/threonine kinases are considered to he the primary Ras effectors uivolved in the
proliferation of animal cells (Avruch et al. (1994) Trends Biochem. Set 19:279).
Raf kinase has three distinct isoforms, Raf-1 (c-Raf), A-Raf, and B-Raf,
distinguished by their ability to interact with Ras, to activate MAPK kinase pathway,
tissue distribution and sub-cellular localization (Marias et al., Biochem. J. 351: 289-305,
10 2000; Weber et. al. Oncogene 19:169-176, 2000; Pritchard et al., Mol. Cell Biol.
15:6430-6442, 1995).
Recent studies have shown that B-Raf mutation in the skin nevi is a critical step in
the mitiation of melanocytic neoplasia (Pollock et. al., Nature Genetics 25: 1-2, 2002).
Furthermore, most recent studies have emerged that activating mutation in the kinase
15 domain of B-Raf occurs in -66% of melanomas, 12% of colon carcinoma and 14% of
liver cancer (Davies et. al.. Nature 417:949-954, 2002) (Yuen et. al., Cancer Research
62:6451-6455, 2002) (Brose et. al.. Cancer Research 62:6997-7000, 2002).
Inhibitors of Raf/MEK/ERK pathway at the level of Raf kinases can potentially be
effective as therapeutic agents against tumors with over-expressed or mutated receptor
20 tyrosine kinases, activated intracellular tyrosine kinases, tumors with aberrantly
expressed Grb2 (an adapter protein tliat allows stimulation of Ras by the Sos exchange
factor) as well as tumors harboring activating mutations of Raf itself. In early clinical
trails an inhibitor of Raf-1 kinase, that also inhibits B-Raf, has shown promise as a
therapeutic agent in cancer therapy (Crump, Current Pharmaceutical Design 8: 2243-
25 2248, 2002; Sebastien et. al.. Current Pharmaceutical Design 8: 2249-2253, 2002).
Disruption of Raf expression in cell lines through the application of RNA
antisense technology has been shown to suppress both Ras and Raf-mediated
tumorigenicity (Kolch etal.. Nature 349:416-428, 1991; Monia etal.. Nature Medicine
2(6):668-675, 1996).
30 Several Raf kinase inhibitors have been described as exhibiting efficacy in
inhibiting tumor cell proliferation in viti'o and/or in vivo assays (see, e.g., U.S. Pat. Nos.
6,391,636, 6,358,932, 6,037,136, 5,717,100, 6,458,813, 6,204,467, and 6,268,391). Other
patents and patent applications suggest the use of Raf kinase inhibitors for treating
wo 2005/037285
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leukemia (see, e.g., U.S. Patent Nos. 6,268,391, and 6,204,467, and published U.S. Patent
Application Nos. 20020137774; 20020082192; 20010016194; and 20010006975), or for
treating breast cancer (see, e,g,, U.S. Patent Nos. 6,358,932, 5,717,100, 6,458,813,
6,268,391, and 6,204,467, and published U.S. Patent Application No. 20010014679).
SUMMARY OF THE INVENTION
New substituted quinazoline, quinoxaline, quinoline and isoquinoline compounds
of are provided of the formula (I) :
wherein, Xi and X2 are independently selected from N or CH, provided that at
least one of Xi and X2 is N;
substituted or unsubstituted amino acid;
Ai is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl,
polycyclic aryl, polycycKc arylalkyl, heteroaryl, biaryl, heteroarylaryl, hetero-
arylheteroaryl, cycloalkylalkyl, cycloalkylaryl, heterocycloalkyl, heterocycloalkylalkyl,
heterocycloaryl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl;
A2 is substituted or unsubstituted aryl or heteroaryl;
Rl is O or H, and R2 is NR^Rv or hydroxyl; or R^ is taken together with R2 to
form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the
dashed Hne represents a single or double bond;
R3 and R3^ are independently selected from hydrogen, halogen, loweralkyl, or
loweralkoxy;
R4 is hydrogen, hydroxyl or substituted or unsubstituted alkyl;
(I)
Y is O, S, CH2, NR5, -N(R5)C(=0)- or -C(=0)N(R5)-;
Z is ^2, NR6R7, NR5(C=0)R8, NR5(C-S)R8, or NR5-AA, wherein AA is a
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R5 is hydrogen, -C(=0)(R5a)-, or substituted or tmsubstitated alkyl, alkoxyalkyl,
aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and
heteroarylalkyU where is substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and
heteroarylalkyl;
and R7 are independently selected from hydrogen, and substituted or
unsubstituted alkyl, alkoxy, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5
and R7 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl;
and
Rg is substituted or unsubstituted alkyl, alkenyl^ alkynyl, alkoxy, amino,
alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaniinoalkyl, cycloalkyl, cycloalkyloxy,
cycloalkylamino, dicycloalkylamino, cycloalkyloxyalkyl, cycloalkylaminoalkyl,
dicycloalkylaminoalkyl, (alkyl)(cycloalkyl)aminoalkyU heterocycloalkyl, heterocyclo-
alkyloxy, heterocycloalkylamino, diheterocycloalkylamino, heterocycloalkyloxyalkyl,
heterocyclo alkylaminoalkyl, (alkyl)(heterocycloalkyl)aminoalkyl, diheterocyloalkyl-
aminoalkyl, aryl, aryloxy, arylamino, diarylamino, aryloxyalkyl, arylaminoalkyl,
diarylaminoalkyl, (alkyl)(aryl)aminoalkyI, heteroaryl, hetero aryloxy, heteroaxylamino,
diheteroarylamino, (alkyl)(heteroaryl)aminoalkyl, heteroaryloxyalkyl, heteroaryl-
aminoalkyl, diheteroarylaminoalkyl, (aryl)(heteroaryl)aminoalkyl or
a stereoisomer, tautomer, prodrug or pliarmaceutically acceptable salt thereof.
hi other embodiments, new substituted quinazoline or isoquinoline compounds are
provided of the formula (II):
wherein Xi, Y, Z, Aj, A2, R3, R3' and R4 are as defined above; or
a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
In other embodiments, new substituted quinazoline and quinoline compounds are
provided of the formula (III) :
(11)
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wherein Xj, Y, Z, A^, A2, R3, R3' and R4 are as defined above; or
a stereoisomer^ tautomer, prodrug or pharmaceutically acceptable salt thereof.
In other embodiments, new substituted quinazoline and quinoxaline compounds
are provided of the formulas (IV) and (IVa):
wherein and Y, Z, A^, A2, R3? R3' and R4 are as defined above; or
a stereoisomer, tautomer, prodrag or pharmaceutically acceptable salt thereof.
In yet other embodiments, new substituted quinazoline, quinoxaUne, quinoline
and isoquinohne compounds are provided of the formula (V):
R4 (V)
wherein X^, X2, X3, Z, A^, R3, R3t and R4 are as defined above; or
a pharmaceutically acceptable salt, ester, or prodmgs thereof.
In yet other embodiments, new substituted quinazoline and isoquinoline
compounds are provided of the formula (VI):
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N
(VI)
wherein X^, A^, R3, R3. and R4 are as defined above; or
a stereoisomer, tautomer^ prodrug or pharmaceutically acceptable salt thereof.
In yet other embodiments, new substituted quinazoline and quinoline compounds
5 are provided of the formula (VII):
(VII)
wherein X2, Aj, R3, R3. and R4 are as defined above; or
a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
In yet other embodiments, new substituted quinazoline and quinoxaline
10 compounds are provided of the formulas (VIII) and (Villa):
(VIII)
(Villa)
wherein A^^ R35 R3' and R4 are as defined above; or
a stereoisomer^ tautomer, prodrug or pharmaceutically acceptable salt thereof.
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Iri other aspects, the present invention provides methods for treating Raf related
disorders in a human or animal subject in need of such treatment comprising
administering to said subject an amount of a compound of formulas (I)-(Vin) effective to
reduce or prevent tumor growth in the subject.
5 In yet other aspects, the present invention provides methods for treating Raf
related disorders in a human or animal subject in need of such treatment comprising
administering to said subject an amount of a compoxmd of formulas (I)-(Vin) effective to
reduce or prevent tumor growth in the subject in combination with at least one additional
agent for the treatment of cancer.
10 In yet other aspects, the present invention provides therapeutic compositions
comprising at least one compound of formulas (I)-(Vin) in combination with one or more
additional agents for the treatment of cancer, as are commonly employed in cancer
therapy.
The compounds of the invention are useful in the treatment of cancers, including
15 carcinomas (e.g., of the lungs, pancreas, thyroid, bladder or colon), myeloid disorders
(e.g., myeloid leukemia) and adenomas (e.g., villous colon adenoma).
The invention further provides compositions, methods of use, and methods of
manufacture as described in the detailed description of the invention.
20 DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In accordance with one aspect of the present invention, new substituted
quinazoline, quinoxaline, quinoline and isoquinoline compoimds and pharmaceutically
acceptable salts, esters or prodrags thereof are provided of the formula (I):
25 wherein, Xi and X2 are independently selected from N or CH, provided that at
least one of Xi and X2 is N;
Y is O, S, CH2, NR5, -N(R5)C(=0)- or -C(=0)N(R5)s
-7-
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Z is NR6R7, NR5(C=0)R8, NR5(C=S)R8, or NR5-AA, wherein AA is a
substituted or unsubstituted amino acid;
Ai is substituted or unsubstituted alkyU cycloalkyl, heterocycloalkyl, aryl,
polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, heteroaryl-
5 heteroaryl, cycloalkylalkyl, cycloalkylaxyl, heterocycloalkyl, heterocycloalkylalkyl,
heterocycloaryl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl;
A2 is substituted or unsubstituted aryl or heteroaryl;
Rl is O or H, and R2 is NR5R7 or hydroxyl; or Rj is taken together with R2 to
form a substituted or imsubstituted heterocycloalkyl or heteroaryl group; wherein, the
1 0 dashed hne represents a single or double bond;
R3 and R3' are independently selected from hydrogen, halogen, loweralkyl, or
loweralkoxy;
R4 is hydrogen, hydroxyl or substituted or unsubstituted alkyl;
R5 is hydrogen, ~C(=0)(R5a)-, or substituted or unsubstituted alkyl, alkoxyalkyl,
15 aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and
heteroarylalkyl, where R^^ is substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and
heteroarylalkyl;
R5 and R7 are independently selected from hydrogen, and substituted or
20 unsubstituted alkyl, alkoxy, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5
and R7 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl;
and
Rg is substituted or imsubstituted alkyl, alkenyl, alkynyl, alkoxy, amino,
25 alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkyloxy,
cycloalkylamino, dicycloalkylamino, cycloalkyloxyalkyl, cycloalkylaminoalkyl,
dicyclo alky lamino alkyl, (alkyl)(cyclo alkyl)aminoalkyl, heterocycloalkyl, hetero-
cycloalkyloxy, heterocycloalkylamino, diheterocycloalkylamino, heterocycloalkyl-
oxyalkyl, heterocycloalkylaminoalkyl, (alkyl)(heterocycloalkyl)aminoalkyl, diheterocylo-
30 alkylaminoalkyl, aryl, aryloxy, arylamino, diarylamino, aryloxyalkyl, arylaminoalkyl,
diarylaminoalkyl, (alkyl)(aryl)aminoalkyl, heteroaryl, heteroaryloxy, heteroarylamino.
-8-
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diheteroarylamino, (alkyl)(heteroaxyl)aminoalkyl, heteroaryloxyalkyl, heteroaryl-
aminoalkyl, diheteroarylaminoalkyl, (aiyl)(heteroaryl)aminoalkyl or
a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
In other embodiments, new substituted quinazoline and isoquinoline compounds
are provided of the formula (II):
wherein Xi, Z, Aj, K^, R3, and R4 are as defined above; or
a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
In other embodiments, new substituted quinazoline and quinoline compounds are
provided of the formula (III):
wherein X2, Y, Z, A^, A2, R3, R3' and R4 are as defined above; or
a stereoisomer, tautomer, prodrag or pharmaceutically acceptable sah thereof
In other embodiments, new substituted quinazoline and quinoxaline compounds
are provided of the formulas (IV) and (IV a):
(11)
(III)
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wherein aiid Y, Aj, A2, R3, R3' and R4 are as defined above; or
a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
In yet other embodiments, new substituted quinazoline, quinoxaline, quinoline
and isoquinoline compounds are provided of the formula (V):
wherein Xj, X2, X3, Z, Aj, R3, R3, and R4 are as defined above; or
a pharmaceutically acceptable salt, ester, or prodrugs thereof.
In yet other embodiments, new substituted quinazoline compounds are provided
of the formula (VI):
^4 (VI)
wherein X^, Z, A^, R3, R3. and R4 are as defined above; or
a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
In yet other embodiments, new substituted quinazoline and quinoline compounds
are provided of the formula (VII):
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R4 (VII)
wherein X2, Ai, R], R2, R3. R3' and R4 are as defined above; or
a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
In yet other embodiments, new substituted quinazoline and quinoxaline
5 compounds are provided of the formulas (VIII) and (Villa):
(VIII)
wherein Z, Ai, R3, Rs- and R4 are as defined above; or
a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
10 In another aspect, the present invention provides methods of treating hxxman or
animal subjects suffering from a Raf related disorder, such as cancer. Thus, the present
invention provides methods of treating a hxmian or animal subject in need of such
treatment comprising administering to the subject a therapeutically effective amount of a
compound of formulas (I)-(VIII) above, either alone or in combination with other
15 anticancer agents.
In other aspects, the present invention provides methods for treating Raf related
disorders in a human or animal subject in need of such treatment comprising
administering to said subject an amount of a compound of formulas (I)-(VIII) effective to
reduce or prevent tumor growth in the subject.
-11-
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In yet other aspects, the present invention provides methods for treating Raf
related disorders in a human or animal subject in need of such treatment comprising
administering to said subject an amount of a compound of formulas (I)-(VIII) effective to
reduce or prevent tumor growth in the subject in combination with at least one additional
agent for the treatment of cancer. A number of suitable anticancer agents to be used as
combination therapeutics are contemplated for use in the methods of the present
invention. Lideed, the present invention contemplates, but is not limited to,
administration of numerous anticancer agents such as: agents that induce apoptosis;
polynucleotides (e.g., ribozymes); polypeptides (e.g., enzymes); drugs; biological
mimetics; alkaloids; alkylating agents; antitumor antibiotics; antimetabolites; hormones;
platinum compounds; monoclonal antibodies conjugated with anticancer drugs, toxins,
and/or radionuclides; biological response modifiers (e.g. interferons [e.g. IFN-a, etc.] and
interleukins [e.g. IL-2, etc.], etc.); adoptive immunotherapy agents; hematopoietic growth
factors; agents that induce tumor cell differentiation (e.g. all-trans-retinoic acid, etc.);
gene therapy reagents; antisense therapy reagents and nucleotides; tumor vaccines;
inhibitors of angiogenesis, and the like. Numerous other examples of chemotherapeutic
compoxxnds and anticancer therapies suitable for coadministration with the disclosed
compounds of formulas (I)-(VIII) are known to those skilled in the art.
In preferred embodiments, anticancer agents to be used in combination with
compounds of the present invention comprise agents that induce or stimizlate apoptosis.
Agents that induce apoptosis include, but are not limited to, radiation; kinase inhibitors
(e.g., epidermal growth factor receptor [EGFR] kinase inhibitor, vascular endothelial
growth factor receptor [VEGFR] kinase inhibitor, fibroblast growth factor receptor
[FGFR] kinase inhibitor, platelet-derived growth factor receptor [PGFR] I kinase
inhibitor, and Bcr-Abl kinase inhibitors such as Gleevec® [imatinib mesylate or STI-
571]); antisense molecules; antibodies [e.g., Herceptin® anti-HER monoclonal antibody
and Rituxan® anti-CD20 monoclonal antibody]; anti-estrogens [e.g., raloxifene and
tamoxifen]; anti-androgens [e.g., flutamide, bicalutamide, finasteride, amino-
glutethamide, ketoconazole, and corticosteroids]; cyclooxygenase 2 (COX-2) inhibitors
[e.g., Celecoxib®, meloxicam, NS-398, and non-steroidal antiinflammatory drugs
(NSAIDs)]; and cancer chemotherapeutic drugs [e.g., irinotecan (Camptosar®), CPT-11,
fludarabine (Fludara®), dacarbazine (DTIC®), dexamethasone, mitoxantrone, Mylotarg®,
VP- 16, cisplatinum, 5-FU, doxombicin, docetaxel (Taxotere®) or taxol, dacarbazine,
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aldesleukin, capecitabine, and Iressa® (gefitinib)]; cellular signaling molecules;
ceramides and cytokines; and staurosprine, and the like.
In other aspects, the present invention provides pharmaceutical compositions
comprising at least one compound of formulas (I)-(VIII) together with a pharmaceutically
5 acceptable carrier suitable for administration to a human or animal subject, either alone or
together with other anticancer agents.
In other aspects, the present invention provides methods of manufacture of
compounds of formulas (I)-(VIII) as described herein.
In yet other aspects, the present invention provides compounds which are
10 inhibitors of the elizyme raf kinase. Since the enzyme is a downstream effector of p2l^^^,
the instant inhibitors are useful in pharmaceutical compositions for human or veterinary
use where inhibition of the raf kinase pathway is indicated, e.g., in the treatment of
tumors and/or cancerous cell growth mediated by raf kinase. In particular, the
compounds are useful in the treatment of hxoman or animal, e.g., murine cancer, since the
15 progression of these cancers is dependent upon the ras protein signal transduction cascade
and therefore is susceptible to treatment by interruption of the cascade by inhibiting raf
kinase activity. Accordingly, the compounds of the invention are useful in treating solid
cancers, such as, for example, carcinomas (e.g., of the Imigs, pancreas, thyroid, bladder or
colon, myeloid disorders (e.g., myeloid leukemia) or adenomas (e.g., villous colon
20 adenoma).
"Raf inhibitor" is used herein to refer to a compound that exhibits an IC50 with
respect to Raf Kinase activity of no more than about 1 00 j^M and more typically not more
than about 50 |liM, as measured in the Raf/Mek Filtration Assay described generally
hereinbelow. Preferred isoforms of Raf Kinase in which the compounds of the present
25 invention will be shown to inhibit, include A-Raf, B-Raf, and C-Raf (Raf-1). "IC50" is
that concentration of inhibitor which reduces the activity of an enzyme (e.g., Raf kinase)
to half-maximal level. Representative compounds of the present invention have been
discovered to exhibit inhibitory activity against Raf Compoxmds of the present invention
preferably exhibit an IC50 with respect to Raf of no more than about 10 |aM, more
30 preferably, no more than about 5 |llM, even more preferably not more than about 1 laM,
and most preferably, not more than about 200 nM, as measured in the Raf kinase assays
described herein.
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The phrase "alkyl" refers to alkyl groups that do not contain heteroatoms. Thus
the phrase includes straight chain alkyl groups such as methyl, ethyl, propyl, butyl,
pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl and the like. The phrase also
includes branched chain isomers of straight chain alkyl groups, including but not limited
5 to, the following which are provided by way of example: -CH(CH3)2,
-CH(CH3)(CH2CH3), -CH(CH2CH3)2, -C(CH3)3, -C(CH2CH3)3, -CH2CH(CH3)2,
-CH2CH(CH3)(CH2CH3), -CH2CH(CH2CH3)2, -CH2C(CH3)3, -CH2C(CH2CH3)3,
-CH(CH3)CH(CH3)(CH2CH3), -CH2CH2CH(CH3)2, -CH2CH2CH(CH3)(CH2CH3),
-CH2CH2CH(CH2CH3)2, -CH2CH2C(CH3)3, -CH2CH2C(CH2CH3)3. -CH(CH3)CH2-
10 CH(CH3)2, -CH(CH3)CH(CH3)CH(CH3)2, -CH(CH2CH3)CH(CH3)CH(CH3)(CH2CH3),
and others. The phrase also includes cyclic alkyl groups such as cyclopropyl, cyclobutyl,
cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl and such rings substituted with
straight and branched chain alkyl groups as defined above. Thus the phrase alkyl groups
includes primary alkyl groups, secondary alkyl groups, and tertiary alkyl groups.
15 Preferred alkyl groups include straight and branched chain alkyl groups and cyclic alkyl
groups having 1 to 12 carbon atoms.
As used herein "loweralkyl" includes both substituted or unsubstituted straight or
branched chain alkyl groups having from 1 to 6 carbon atoms. Representative loweralkyl
groups include, for example, methyl, ethyl, propyl, isopropyl, /2-butyl, tert-butyl,
20 neopentyl, trifluoromethyl, pentafluoroethyl and the like. Loweralkyl groups may be
substituted, such as with halo, hydroxy, amino, nitro and/or cyano groups, and the like.
Representative of halo-substituted and hydroxy-substituted loweralkyl include
chloromethyl, trichloromethyl, chloroethyl, hydroxyethyl, and the like. Other suitable
substituted loweralkyl moieties include, for example, aralkyl, aminoalkyl, aminoarallcyl,
25 carbonylaminoalkyl, alky Icarbonylamino alkyl, arylcarbonylaminoalkyl, aralkylcarbonyl-
aminoalkyl, aminoalkoxyalkyl and arylaminoalkyl.
"Loweralkoxy" as used herein refers to RO- wherein R is loweralkyl.
Representative examples of loweralkoxy groups include methoxy, ethoxy, ^butoxy,
trifluoromethoxy and the like.
30 As used herein, the term "halogen" or "halo" refers to chloro, bromo, fluoro and
iodo groups. "Haloalkyl" refers to an alkyl radical substituted with one or more halogen
atoms. The term "haloloweralkyl" refers to a loweralkyl radical substituted with one or
more halogen atoms. The term "haloalkoxy" refers to an alkoxy radical substituted with
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one or more halogen atoms. The term "haloloweralkoxy" refers to a loweralkoxy radical
substituted with one or more halogen atoms.
"Amino" refers herein to the group — NH2. The term "alkylamino" refers herein to
the group — NRR^ where R and are each independently selected from hydrogen or a
5 lower alkyl. The term "arylamino" refers herein to the group — NRR' where R is aryl and
R' is hydrogen, a lower alkyl, or an aryl. The term "aralkylamino" refers herein to the
group -NRR' where R is a lower aralkyl and R' is hydrogen, a loweralkyl, an aryl, or a
loweraralkyl.
The tenn amino acid refers to both alpha and beta amino acids having D- or
1 0 L-stereochemistry, and includes, but is not limited to, synthetic, non-natural amino acids
having side chains other than those found in the 20 common amino acids. Non-natural
amino acids are commercially available or may be prepared according to US 5,488,131
and references therein. Amino acids may be further substituted to contain modifications
to their amino, carboxy, or side chain groups. These modifications include the numerous
1 5 protecting groups commonly used in peptide synthesis.
The term "alkoxyalkyl" refers to the group "-alki-0-alk2 where alki is alkyl or
alkenyl, and alk2 is alkyl or alkenyl. The term "loweralkoxyalkyl" refers to an
alkoxyalkyl where alki is loweralkyl or loweralkenyl, and alkz is loweralkyl or
loweralkenyl. The term "aryloxyalkyl" refers to the group -alkyl-O-aryl. The term
20 "ar alkoxyalkyl" refers to the group -alkylenyl-O-aralkyl, where aralkyl is a loweraralkyl.
The term "alkoxyalkylamino" refers herein to the group ~NR-(alkoxyalkyl),
where R is typically hydrogen, loweraralkyl, or loweralkyl. The term
"aminolower alkoxyalkyl" refers herein to an aminoalkoxyalkyl in which the alkoxyalkyl
is a lower alkoxyalkyl.
25 The term "aminocarbonyl" refers herein to the group — C(0)-NH2 . "Substituted
aminocarbonyl" refers herein to the group -C(0)-NRR' where R is loweralkyl and R' is
hydrogen or a loweralkyl. The term "arylaminocarbonyl" refers herein to the group
-C(0)-NRR' where R is an aryl and R^ is hydrogen, loweralkyl or aryl.
"aralkylaminocarbonyl" refers herein to the group ~-C(0)-NRR' where R is loweraralkyl
30 and R is hydrogen, loweralkyl, aryl, or loweraralkyl.
"Aminosulfonyl" refers herein to the group -S(0)2-NH2. "Substituted
aminosulfonyl" refers herein to the group -S(0)2-NRR' where R is loweralkyl and R* is
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hydrogen or a loweralkyl. The term "aralkylaminosulfonlyaryl" refers herein to the group
-aryl-S(0)2-NH-aralkyl, where the aralkyl is loweraralkyl.
"Carbonyr^ refers to the divalent group -C(0)-.
"Carbonyloxy" refers generally to the group -C(0)-0. Such groups include
5 esters, -C(0)-0-R, where R is loweralkyl, cycloalkyl, aryl, or loweraralkyl. The term
"carbonyloxycycloalkyl" refers generally herein to both a "carbonyloxycarbocycloalkyl"
and a "carbonyloxyheterocycloalkyl", i.e., where R is a carbocycloalkyl or
heterocycloalkyl, respectively. The term "arylcarbonyloxy" refers herein to the group -
C(0)-0-aryl, where aryl is a mono- or polycyclic, carbocycloaryl or heterocycloaryl. The
10 terni "aralkylcarbonyloxy" refers herein to the group -C(0)-0-aralkyl, where the aralkyl
is loweraralkyl.
The term "sulfonyl" refers herein to the group -SO2-. "Alkylsulfonyl" refers to a
substituted sulfonyl of the structure -SO2R- in which R is alkyl. Alkylsulfonyl groups
employed in compoimds of the present invention are typically loweralkylsulfonyl groups
1 5 having from 1 to 6 carbon atoms in its backbone structure. Thus, typical alkylsulfonyl
groups employed in compoimds of the present invention include, for example,
methylsulfonyl (i.e., where R is methyl), ethylsulfonyl (i.e., where R is ethyl),
propylsulfonyl (i.e., where R is propyl), and the hke. The term "arylsulfonyl" refers
herein to the group -SOi-aryl. The term "aralkylsulfonyl" refers herein to the group
20 -S02-aralkyl, in which the aralkyl is loweraralkyl. The term "sulfonamido" refers herein
to -SO2NH2.
As used herein, the tenn "carbonylamino" refers to the divalent group -NH-C(O)-
in which the hydrogen atom of the amide nitrogen of the carbonylamino group can be
replaced a loweralkyl, aryl, or loweraralkyl group. Such groups include moieties such as
25 carbamate esters (-NH-C(O)-O-R) and amides ™NH-C(0)-0-R, where R is a straight or
branched chain loweralkyl, cycloalkyl, or aryl or loweraralkyl. The term
"loweralkylcarbonylamino" refers to alkylcarbonylamino where R is a loweralkyl having
from 1 to about 6 carbon atoms in its backbone structure. The term "arylcarbonylamino"
refers to group -NH-C(0)-R where R is an aryl. Sknilarly, the term
30 "aralkylcarbonylamino " refers to carbonylamino where R is a lower aralkyl. As used
herein, the term " amino carbonyl" refers to the divalent group -C(0)-NH- in which the
hydrogen atom of the amide nitrogen of the carbonylamino group can be replaced a
loweralkyl, aryl, or loweraralkyl group, as described above,
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As used herein, the term "guanidino^' or "guanidyl" refers to moieties derived
from guaxiidine, H2N-C(=NH)-NH2. Such moieties include those bonded at the nitrogen
atom carrying the formal double bond (the "2"-position of the guanidine, e.g.,
diaminomethyleneamino, (H2N)2C=NH-) and those bonded at either of the nitrogen
5 atoms carrying a formal single bond (the "1-" and/or '3 "-positions of the guandine, e.g.,
H2N-C(=NH)-NH-). The hydrogen atoms at any of the nitrogens can be replaced with a
suitable substituent, such as loweralkyl, aryl, or loweraralkyl.
As used herein, the term "amidino" refers to the moieties R'-C(=N)-NR'" (the
radical being at the ^'N^" nitrogen) and R(NR')C=N- (the radical being at the "N^"
1 0 nitrogen), where R and R' can be hydrogen, loweralkyl, aryl, or loweraralkyl.
"Cycloalkyl" refers to a mono- or polycyclic, heterocychc or carbocyclic alkyl
substituent. Typical cycloalkyl substituents have from 3 to 8 backbone (i.e., ring) atoms
in which each backbone atom is either carbon or a heteroatom. The term
"heterocycloalkyl" refers herein to cycloalkyl substitaents that have from 1 to 5, and more
15 typically from 1 to 4 heteroatoms in the ring structure. Suitable heteroatoms employed in
compounds of the present invention are nitrogen, oxygen, and sulfiir. Representative
heterocyclo alkyl moieties include, for example, morpholino, piperazinyl, piperadinyl and
the like. Carbocycloalkyl groups are cycloalkyl groups in which all ring atoms are
carbon. When used in connection with cycloalkyl substituents, the term "polycyclic"
20 refers herein to fused and non-fiised alkyl cychc stmctures. Examples of such polycychc
stmctures include bicyclic compoxmds having two bridgehead atoms connected by three
or more arms. An example of a bicyclic structure is bicyclo[2.2.1] heptane, in which the
bridgehead atoms are connected by three arms respectively having two, two, and one
carbon atoms.
25 The term "substituted heterocycle" or "heterocyclic group" or heterocycle as used
herein refers to any 3- or 4-membered ring containing a heteroatom selected from
nitrogen, oxygen, and sulfur or a 5- or 6-membered ring containing from one to three
heteroatoms selected from the group consisting of nitrogen, oxygen, or sulfur; wherein
the 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double
30 bonds; wherein the nitrogen and sulfrir atom maybe optionally oxidized; wherein the
nitrogen and sulftir heteroatoms maybe optionally quartemized; and including any
bicyclic group in which any of the above heterocyclic rings is fiised to a benzene ring or
another 5- or 6-membered heterocyclic ring independently defined above. The term
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"heterocycle" thus includes rings in which nitrogen is the heteroatom as well as partially
and fully-saturated rings. Preferred heterocycles include, for example: diazapinyl, pyrryl,
pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazoyl, imidazolinyl,
imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazkiyl, N-methyl piperazinyl,
azetidinyl, N-methylazetidinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl,
isoxazolyl, isoazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl,
isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl,
benzoxazolyl, furyl, thienyl, triazolyl and benzothienyL
Heterocyclic moieties can be unsubstituted or monosubstituted or disubstituted
with various substituents independently selected from hydroxy, halo, oxo (C=0),
alkylimino (RN=, wherein R is a loweralkyl or loweralkoxy group), amino, alkylamino,
dialkylamino, acylaminoalkyl, alkoxy, thioalkoxy, polyalkoxy, loweralkyl, cycloalkyl or
haloalkyl.
The heterocyclic groups may be attached at various positions as will be apparent
to those having skill in the organic and medicinal chemistry arts in conjunction with the
disclosiore herein.
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o
o
and
where R is H or a heterocyclic substituent, as
described herein.
Representative heterocyclics include, for example, hnidazolyl, pyridyl,
piperazinyl, azetidinyl, thiazolyl, furanyl, triazolyl benzimidazolyl, benzothiazolyl,
5 benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl, indolyl,
naphthpyridinyl, indazolyU and quinolizinyL
"Aryl" refers to optionally substituted monocyclic and polycyclic aromatic groups
having from 3 to 14 backbone carbon or hetero atoms, and includes both carbocyclic aryl
groups and heterocyclic aryl groups. Carbocyclic aryl groups are aryl groups in which all
10 ring atoms in the aromatic ring are carbon. The term "heteroaryl" refers herein to aryl
groups having from 1 to 4 heteroatoms as ring atoms in an aromatic ring with the
remainder of the ring atoms being carbon atoms. When used in connection with aryl
substituents, the term "polycyclic aryl" refers herein to fused and non-fused cyclic
structures in which at least one cyclic structure is aromatic, such as, for example,
15 benzodioxozolo (which has a heterocyclic structure fused to a phenyl group, i.e..
o^""^ ^ naphthyl, and the like. Exemplary aryl moieties employed as substituents in
compoxmds of the present invention include phenyl, pyridyl, pyrimidinyl, thiazolyl,
indolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyrazinyl, triazolyl, thiophenyl, furanyl,
quinolinyl, purinyl, naphthyl, benzothiazolyl, benzopyridyl, and benzimidazolyl, and the
"Aralkyl" refers to an alkyl group substituted with an aryl group. Typically,
aralkyl groups employed in compounds of the present invention have from 1 to 6 carbon
atoms incorporated within the alkyl portion of the aralkyl group. Suitable aralkyl groups
employed in compounds of the present invention include, for example, benzyl, picolyl,
25 and the like.
Representative heteroaryl groups include, for example, those shown below. These
heteroaryl groups can be further substituted and may be attached at various positions as
will be apparent to those having skill in the organic and medicinal chemistry arts in
conjimction with the disclosure herein.
20
like.
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5
Representative heteroaryl groups include, for example, imidazolyU pyridyl,
piperazinyl, azetidinyl, thiazolyl, triazolyl benzimidazolyl, benzothiazolyl, benzoxazolyl,
pyrazolyl and pyrazinyl.
The term "biaryl" refers to a group or substituent to which two aryl groups, which
10 are not condensed to each other, are bound. Exemplary biaryl compounds include, for
example, phenylbenzene, diphenyldiazene, 4-methylthio-l -phenylbenzene, phenoxy-
benzene, (2-phenylethynyl)benzene, diphenyl ketone, (4-phenylbuta-l,3-diynyl)benzene,
phenylbenzylamine, (phenylmethoxy)benzene, and the like. Preferred optionally
substituted biaryl groups include; 2-(phenylamino)-N-[4-(2-phenylethynyl)phenyl]-
15 acetamide, 1 ,4-diphenylbenzene, N-[4-(2-phenylethynyl)phenyl]-2-[benzylamino]-
acetamide, 2-amino-N-[4-(2-phenylethynyl)phenyl]propanamide, 2-amino-N-[4-(2-
phenylethynyl)phenyl]acetamide, 2-(cyclopropylamino)-N-[4-(2-phenylethynyl)phenyl]-
acetamide, 2-(ethylamino)-N-[4-(2-phenylethynyl)phenyl]acetamide, 2-[(2-methyl-
propyl)amino]-N-[4-(2-phenylethynyl)phenyl]acetamide, 5-phenyl-2H-benzo[d] 1 ,3-
20 dioxolene, 2-chloro-l-methoxy-4-phenylbenzene, 2-[(imidazolylmethyl)amino]-N-[4-(2-
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phenylefhynyl)phenyl]acetamide, 4-phenyl-l-phenoxybenzene, N"(2-ammoethyl)[4-(2-
phenylethynyl)phenyl] carboxamide, 2- { [(4-fluorophenyl)methyl] amino} -N- [4-(2"phenyl-
ethynyl)pheiiyl]acetamide, 2-{[(4-methylphenyl)methyl]amino}-N-[4<2-phenylethy
phenyl]acetamide, 4-phenyl-l-(trifluoromethyl)benzene, 1 -butyl-4-phenylbenzene, 2-
5 (cyclohexylamino)-N--[4-(2-phenylethynyl)phenyl]acetamide, 2-(ethylmethylainino)-N-
[4-(2-phenylethynyl)phenyl]acetamide, 2-(butylainino)-N-[4-(2-phenylethynyl)phenyl]-
acetamide, N-[4-(2-phenylethynyl)phenyl]-2-(4-pyridylamino)acetamide, N-[4-(2-
phenylethynyl)phenyl]-2<quinuclidin-3-ylamino)acetamide, N-[4-(2-plienylethyiiyl)-
phenyl]pyrrolidin-2-ylcarboxamide, 2-amino-3-methyl-N-[4-(2-phenylethynyl)plienyl]-
1 0 butanamide, 4-(4-phenylbuta- 1 ,3 -diynyl)phenylamine, 2-(dimethylammo)-N-[4-(4-
phenylbuta-l,3-diynyl)phenyl]acetamide, 2-(ethylamino)-N-[4-(4-phenylbuta-13-
diynyl)phenyl]acetamide, 4-ethyl- 1 -phenylbenzene, 1 -[4-(2-phenylethynyl)phenyl]ethan-
1 -one, N-(l -carbamoyl-2-hydroxypropyl)[4-(4-phenylbuta- 1 ,3-diynyl)phenyl]carbox-
amide, N-[4-(2-phenylethynyl)phenyl]propanamide, 4-methoxyphenyl phenyl ketone,
1 5 phenyl-N-benzamide, (tert-butoxy)-N4(4-phenylphenyl)methyl]carboxamide, 2<3-
phenylphenoxy)ethanehydroxaniic acid, 3-phenylphenyl propanoate, 1 -(4-ethoxyphenyl)-
4-methoxybenzene, and [4"(2-phenylethynyl)phenyl]pyrrole.
The term "heteroarylaryl" refers to a biaryl group where one of the aryl groups is a
heteroaryl group. Exemplary heteroarylaryl groups include, for example, 2-phenyl-
20 pyridine, phenylpyrrole, 3-(2-phenylethynyl)pyridine, phenylpyrazole, 5-(2-phenyl-
ethynyl)- 1 ,3 -dihydropyrimidine-2,4-dione, 4-phenyl- 1 ,2 ,3-thiadiazole, 2-(2-phenyl-
ethynyl)pyrazine, 2-phenylthiophene, phenylimidazole, 3-(2-piperazinylphenyl)furan, 3-
(2,4-dichlorophenyl)-4-methylpyrrole, and the like. Preferred optionally substituted
heteroarylaryl groups include: 5-(2-phenylethynyl)pyrimidine-2-ylamine, l-methoxy-4-
25 (2-thienyl)benzene, l-methoxy-3-(2-thienyl)benzene, 5-methyl-2-phenylpyridine, 5-
methyl-3 -phenylisoxazole, 2- [3 -(trifluoromethy l)phenyl] fur an, 3 -fluoro-5 -(2-furyl)-2-
methoxy- 1 -prop-2-enylbenzene, (hydroxyimino)(5-phenyl(2-thienyl))methane, 5-[(4-
methylpiperazinyl)methyl]-2-phenylthiophene, 2-(4-ethylphenyl)thiophene, 4-methylthio-
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1 -(2-thienyl)benzene, 2-(3 -mtrophenyl)thiophene, (tert-butoxy)-N-[(5-phenyl(3-pyridyl))-
methyl] carboxamide, by droxy-N- [(5 -phenyl(3 -pyridyl))mefhyl] amide, 2-(phenylmethyl-
thio)pyridine, and benzylimidazole.
The terai "heteroarylheteroaryl" refers to a biaryl group where both of the aryl
5 groups are a heteroaryl group. Exemplary heteroarylheteroaryl groups include, for
example, 3-pyridylimidazole, 2-imidazolylpyrazine, and the like. Preferred optionally
substituted heteroarylheteroaryl groups include: 2-(4-piperazinyl"3-pyridyl)ftiran, diethyl-
(3 -pyrazin-2-yl(4-pyridyl))amine, and dimethyl { 2- [2- (5-methylpyrazin-2'-yl)ethynyl] (4-
pyridyl) } amine .
10 "Optionally substituted" or "substituted" refers to the replacement of hydrogen
with a monovalent or divalent radical. Suitable substitution groups include, for example,
hydroxyl, nitro, amino, imino, cyano, halo, thio, sulfonyl, thioamido, amidino, imidino,
oxo, oxamidino, methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl,
loweralkyl, haloloweralkyl, loweralky amino, haloloweralkylamino, loweralkoxy,
1 5 haloloweralkoxy, loweralkoxyalkyl, alkylcarbonyl, aminocarbonyl, arylcarbonyl,
aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyU alkylthio, aminoalkyl,
cyanoalkyl, aryl and the like. The term substituted and unsubstituted, when introducing a
list of substituents, is intended to apply to each member of that list. For instance the
phrase "substituted and unsubstituted aryl, heteroaryl, or alkyl" and the phrase
20 "substituted and imsubstituted aryl, heteroaryl, and alkyl" is intended to specify aryl,
heteroaryl, and alky groups that are each substituted or unsubstituted.
The substitution group can itself be substituted. The group substituted onto the
substitution group can be carboxyl, halo; nitro, amino, cyano, hydroxyl, loweralkyl,
loweralkoxy, aminocarbonyl, -SR, thioamido, -SO3H, -SO2R or cycloalkyl, where R is
25 typically hydrogen, hydroxyl or loweralkyl.
When the substituted substituent includes a straight chain group, the substitution
can occur either within the chain (e.g., 2'"hydroxypropyl, 2-aminobutyl, and the like) or at
the chain terminus (e.g., 2-hydroxyethyl, 3-cyanopropyl, and the like). Substituted
substitutents can be straight chain, branched or cyclic arrangements of covalently bonded
3 0 carbon or bet ero atoms ,
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As used herein, the term "carboxy-protecting group" refers to a carbonyl group
which has been esterified with one of the commonly used carboxylic acid protecting ester
groups employed to block or protect the carboxylic acid function while reactions
involving other functional sites of the compound are carried out. In addition, a carboxy
5 protecting group can be attached to a solid support whereby the compound remains
connected to the solid support as the carboxylate imtil cleaved by hydrolytic methods to
release the corresponding free acid. Representative carboxy-protecting groups include,
for example, loweralkyl esters, secondary amides and the like.
As used herein, the term "pharmaceutically acceptable salts" refers to the nontoxic
1 0 acid or alkaline earth metal salts of the compounds of Formula L These salts can be
prepared in situ during the final isolation and purification of the compounds of Formula I,
or by separately reacting the base or acid functions with a suitable organic or inorganic
acid or base, respectively. Representative salts include but are not limited to the
following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate,
15 bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate,
dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate,
heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide,
2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-napth-
alenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproionate, picrate,
20 pivalate, propionate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate and
undecanoate. Also, the basic nitrogen-containing groups can be quatemized with such
agents as loweralkyl halides, such as methyl, ethyl, propyl, and butyl cUoride, bromides,
and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long
chain halides such as decyl, la"uryl, myristyl and stearyl chlorides, bromides and iodides,
25 aralkyl halides like ben2yl and phenethyl bromides, and others. Water or oil-soluble or
dispersible products are thereby obtained.
Examples of acids which may be employed to form pharmaceutically acceptable
acid addition salts include such inorganic acids as hydrochloric acid, sulfioric acid and
phosphoric acid and such organic acids as oxalic acid, maleic acid, methanesulfonic acid,
30 succinic acid and citric acid, Basic addition salts can be prepared in situ dxiring the final
isolation and purification of the compounds of formula (I), or separately by reacting
carboxylic acid moieties with a suitable base such as the hydroxide, carbonate or
bicarbonate of a pharmaceutically acceptable metal cation or with ammonia, or an
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organic primary, secondary or tertiary amine. Pharmaceutically acceptable salts include,
but are not limited to, cations based on the alkali and alkaline earth metals, such as
sodium, lithium, potassiimi, calciimi, magnesium, aluminum salts and the like, as well as
nontoxic ammonium, quatemary ammonium, and amine cations, including, but not
5 limited to ammonium, tetramethylammonium, tetraethylammonium, methylamine,
dimethylamine, trimethylamine, triethylamine, ethylamine, and the like. Other
representative organic amines useful for tlie formation of base addition salts include
diethylamine, ethylenediamine, ethanolamine, diethanolamine, piperazine and the like.
As used herein, the term "pharmaceutically acceptable ester" refers to esters,
1 0 which hydrolyze in vivo and include those that break down readily in the hxmian body to
leave the parent compound or a salt thereof. Suitable ester groups include, for example,
those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly
alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl
moiety advantageously has not more than 6 carbon atoms. Examples of particular esters
15 include formates, acetates, propionates, butyrates, acrylates and ethylsuccinates.
The term "pharmaceutically acceptable prodmgs" as used herein refers to those
prodrugs of the compounds of the present invention which are, within the scope of sound
medical judgment, suitable for use in contact with the tissues of humans and lower
animals without undue toxicity, irritation, allergic response, and the like, commensurate
20 with a reasonable benefit/risk ratio, and effective for their intended use, as well as the
zwitterionic fonns, where possible, of the compounds of the invention. The term
"prodmg" refers to compoxmds that are rapidly transformed in vivo to yield the parent
compound of the above formula, for example by hydrolysis in blood. A thorough
discussion is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems,
25 Vol. 14 of the A.C.S. Symposium Series, and in Edward B. Roche, ed., Bioreversible
Carriers in Drug Design, American Pharmaceutical Association and Pergamon Press,
1987, both of which are incorporated herein by reference.
The term "cancer" refers to cancer diseases that can be beneficially treated by the
inhibition of Raf kinase, including, for example, solid cancers, such as carcinomas (e.g.,
30 of the lungs, pancreas, thyroid, bladder or colon), myeloid disorders (e.g., myeloid
lexikemia) and adenomas (e.g., villous colon adenoma).
In illustrative embodiments of the invention, Aj may be, for example, phenyl,
phenylalkyl, pyridyl, pyrimidinyl, pyridylalkyl, pyrimidinylalkyl, alkylbenzoate,
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thiophene, tliiopIiene-2-carboxylate, indenyl, 23-dihydroindenyl, tetralinyl,
triflourophenyl, (triflouromethyl)thiophenyl, morpholinyl, N-piperazinyU N-
morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-dihydroindolyl, 1-
aceytl-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2.1]hept-2-yl, pyrrolidinyl, pyrrolidin-
1-yl, pyrrolidin-1-ylalkyl, 4-amino(iinino)methylphenyl, isoxazolyl, indazolyl,
adamantyl, bicycloliexyl, quinuclidinyl, imidazolyl, benzimidazolyl, imidazolylphenyl,
phenylimidazolyl, pthalamido, napthyl, napththalenyl, benzophenone, aiiilinyl, anisolyl,
quinolinyl, quinolinonyl, phenylsulfonyl, phenylalkylsulfonyl, 9H-flotiren- 1 -yl, piperidin-
1-yl, piperidin-1-ylalkyl, cyclopropyl, cyclopropylalkyl, furanyl, N-methylpiperidin-4-yl,
pyrrolidin-4-ylpyridinyl, 4-diazepan-l-yl, hydroxypyrrolidn-l-yl, dialkylaminopyrrolidin-
1-yl, and 1,4 -bipiperidin-r-yl, wMch may be substituted by one or more substitutents
selected from the group consisting of hydroxyl, nitro, cyano, halo, and substituted or
unsubstituted amino, imino, thio, sulfonyl, thioamido, amidino, imidino, oxo, oxamidino,
methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, loweralkyl,
haloloweralkyl, loweralkyamino, haloloweralkylamino, loweralkoxy, haloloweralkoxy,
loweralkoxyalkyl, alkylcarbonyl, aminocarbonyl, loweralkylaminocarbonyl, hetero-
cycloalkylloweralkylaminocarbonyl, carboxylloweralkylaminocarbonyl, arylcarbonyl,
aralkylcarbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl,
cyanoalkyl, aryl and the like. In other embodiments, may be substituted phenyl, such
as, for example, substituted or unsubstituted hydroxyphenyl, hydroxyalkylphenyl, alkyl-
phenyl, dialkylphenyl, trialkylphenyl, alkoxyphenyl, dialkoxyphenyl, alkoxyalkylphenyl,
halophenyl, dihalophenyl, haloalkylphenyl, haloalkoxyphenyl, alkylhalophenyl, alkoxy-
halophenyl, alkylthiophenyl, aminophenyl, nitrophenyl, acetylphenyl, sulfamoylphenyl,
biphenyl, alkoxybiphenyl, cyclohexylphenyl, phenyloxyphenyl, dialkylaminophenyl,
morpholinylphenyl, heterocyclylcarbonylphenyl, heterocyclylphenyl, lieterocyclylalkyl-
phenyl, furanylphenyl, (l,4-bipiperidin-r-ylcarbonyl)phenyl, pyrimidin-5-ylphenyl, and
quinolidinylphenyl. In yet other embodiments, Aj is substituted phenyl selected from the
group consisting of chlorophenyl, flourophenyl, bromophenyl, iodophenyl, dichloro-
phenyl, difluorophenyl, dibromophenyl, flurorchlorophenyl, bromocMorophenyl,
trifluoromethylphenyl, trifluoromethoxyphenyl, alkylbromophenyl, trifluoromethyl-
bromophenyl, alkylchlorophenyl, triflouromethylchlorophenyl, alkylflourophenyl, aad
triflouromethylfluorophenyl.
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In other illustrative embodiments of the invention, A2 is substituted or
unsubstituted aryl or heteroaryl, such as, for example, substituted or unsubstituted phenyl,
pyridyl, pyrimidinyl, thiazolyl, indolyl, imidazolyl, oxadiazolyl, tetrazolyl, pyrazinyl,
triazolyl, thiophenyl, furanyl, quinolinyl, ptirinyl, naphthyl, benzothiazolyl, benzopyridyl,
and benzimidazolyl, and the like, which may be substituted by one or more substitutents
selected from the group consisting of hydroxyl, nitro, cyatio, halo, and substituted or
unsubstituted amino, imino, thio, sulfonyl, thioamido, amidino, imidino, 0x0, oxamidino,
methoxamidino, imidino, guanidino, sulfonamido, carboxyl, formyl, loweralkyl,
haloloweralkyl, loweralkyamino, haloloweralkylamino, loweralkoxy, haloloweralkoxy,
loweralkoxyalkyl, alkylcarbonyl, aminocarbonyl, loweralkylaminocarbonyl, heterocyclo-
alkylloweralkylaminocarbonyl, carboxyllov^eralkylaminocarbonyl, arylcarbonyl, aralkyl-
carbonyl, heteroarylcarbonyl, heteroaralkylcarbonyl, alkylthio, aminoalkyl, cyanoalkyl,
aryl and the like. In other representative embodiments of the invention, A2 is substituted
or imsubstituted pyridyl.
In representative embodiments of the invention, the compounds of the invention
include, for example, 4-{2-[(4-bromophenyl)amino]quinazolin-6-yloxy}-(2-pyridyl)-N-
methylcarboxamide, N-methyl-4- { [2-({4- [(trifluoromethyl)oxy]phenyl } amino)-
quinazolin-6-yl]oxy}pyridine-2-carboxamide, N-methyl-4- [(2- { [4-(trifluoromethyl)-
phenyl]amino}quinazolin-6-yl)oxy]pyridine-2-carboxamide, 4-[(2-{[2-fluoro-5-(tri-
fluoromethyl)phenyl] amino } quinazolin-6-yl)oxy] -N-methylpyridine-2- carboxamide, N-
methyl-4-[(2- { [3 -(trifluoromethyl)phenyl] amino } quinazolin-6-yl)oxy]pyridine-2-
carboxamide, 4-( {2- [(4-bromo-3 -methylphenyl)amino] quinazolin-6-yl} oxy)-N-methyl-
pyridine-2-carboxamide, 4- [(2- { [4-fluoro-3 -(trifluoromethyl)phenyl] amino } quinazolin-6-
yl)oxy] -N-methylpyridine-2-carboxamide, N-methyl-4- [(2- { [4-(methylthio)phenyl] -
amino}quinazolin-6-yl)oxy]pyridine-2-carboxamide, N-methyl-4-{[2-({4-[(phenyl-
methyl) oxyjphenyl } amino)quinazolin-6-yl] oxy ) pyridine-2-carboxamide, N-methyl-4-
({2-[(4-morpholin-4-ylphenyl)amino]quinazolin-6-yl}oxy)pyridine-2-carboxamide, 4-
({2-[(6-chloropyridin-3-yl)amino]quinazolin-6-yl}oxy)-N-methylpyridine-2-carbox-
amide, 4-[(2-{[4-chloro-3-(trifluoromethyl)phenyl]amino}quinazolin-6-yl)oxy]-N-
methylpyridine-2-carboxamide, 4-({2-[(3,5-dichlorophenyl)amino]quinazolin-6-yl}oxy)-
N-methylpyridine-2-carboxamide, N-methyl-4-[(2-{[6-(methyloxy)pyridin-3-yl] amino }-
quinazolin-6-yl)oxy]pyridine-2-carboxamide, N-methyl-4- { [2-(phenylamino)quinazolin-
6-yl]oxy}pyridine-2-carboxamide, 4-{[2-(bicyclo[2.2,l]hept-2-ylamino)quinazolin-6-yl]-
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oxy } -N-methylpyridine-2-carboxaimde, 4- { [2-(cyclohexylamino)qumazolin-6-yl]oxy } -
N-methylpyridine-2-carboxamide, N-methyl-4-({2-[(phenylmethyl)amino]quinazolin-6-
yl } oxy)pyridine-2-carboxamide, N-methyl-4-( {2- [(2-phenylethyl)amino] quinazolin-6-
yl } oxy)pyridine-2-carboxamide, 4- [(2- { [( 1 -ethylpyrTolidin-2-yl)methyl] amino } -
quinazolin-6-yl)oxy]-N-methylpyridine-2-carboxamide, 4-[(2-{ [2-bromo-4-(l -methyl-
ethyl)phenyl]ammo}quinazolin-6-yl)oxy]-N-methylpyridine-2-c^^ 4-{{2-[(4~
bromo-2-fluorophenyl)amino]qmnazolin-6-yl}oxy)-N-me1iiylpyridin^ N-
methyl[4-(2-methylsulfonylquinazolin-6-yloxy)(2-pyridyl)]carboxamide, N-methyl-4-
{ [2-( {4- [(trifluoromethyl)oxy] phenyl} amino) quinazolin-6-yl] oxy }pyTidine-2-
carboxamide, N-methyl-4- [(2- { [4-(trifluoromethyl)phenyl] amino } qmnazolin-6-
yl)oxy]pyridine-2-carboxamide, 4-[(2-{[2-fluoro-5-(trifluoromethyl)phenyl]amino}-
quinazolin-6-yl)oxy]-N-methylpyridine-2-carboxamide, N-methyl-4- [(2- {[3 -(trifluoro-
methyl)phenyl]amino}quinazoHn-6-yl)oxy]pyridine-2-carboxamide, 4-({2-[(4-bromo-3-
methylphenyl)aniino] qurnazolin-6-yl} oxy)-N-methylpyridine-2-carboxamide, 4- [(2- { [4-
fluoro-3-(trifluoromethyl)phenyl] amino } quinazolin-6-yl)oxy] -N-metliylpyridine-2-
carboxamide, N-methyl-4- [(2- { [4-(methylthio)phenyl] amino } quinazolin-6-yl)oxy] -
pyridine-2-carboxamide, N-methyl-4- { [2-( {4- [(phenylmethyl)oxy]phenyl} amino)-
quina2:olin-6-yl]oxy}pyridine-2-carboxamide, N-methyl-4-({2-[(4-morpholin-4-yl-
phenyl)amino]quinazolin-6-yl}oxy)pyridine-2-carboxamide, 4-({2-[(6-chloropyridin-3-
yl)amino]quinazolin-6-yl}oxy)-N-methylpyridine-2-carboxamide, 4-[(2-{[4-chloro-3-
(trifluoromethyl)phenyl]amino}quinazolin-6-yl)oxy]-N-methylpyridine-2-carboxamide,
4-({2-[(3,5-dichlorophenyl)amino]quinazolin-6-yl}oxy)-N-methylpyridine-2-
carboxamide, N-methyl-4- [(2- { [6-(methyloxy)pyridin-3 -yl] ainino } quinazolin-6-yl)oxy] -
pyridine-2-carboxamide5 N-methyl-4- { [2-(phenylamino)quinazolin-6-yl]oxy }pyridine-2-
carboxamide, 4- { [2-(bicyclo [2.2. 1 ]hept-2-ylamino)quinazoHn-6-yl]oxy } -N-methyl-
pyridine-2-carboxamide, 4- { [2-(cyclohexylamino)quinazolin-6-yl]oxy } -N-methyl-
pyridine-2-carboxamide5 N-methyl-4-({2-[(phenylmethyl)amino]quinazolin-6-yl}oxy)-
pyridine-2-carboxamide, N-methyl-4-( {2- [(2-phenylethyl)amino] quinazolin-6-yl } oxy)-
pyridine-2-carboxamide, 4-[(2- { [( 1 -ethylpyrrolidin-2-yi)methyl] amino } quinazolin-6-yl)-
oxy]-N-methylpyridine-2-carboxamide, 4-[(2-{ [2-bromo-4-(l -methylethyl)phenyl]-
amino}quinazolin-6-yl)oxy]-N-methylpyridine-2-carboxamide, 4-({2-[(4-bromo-
2-fluorophenyl)amino]qmnazolin-6-yl}oxy)-N-methylpyridine-2-carboxamide,
4-({2-[(254-dichlorophenyl)amino]quinazolin-6-yl}oxy)-N-methylpyridine-2-carbox-
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amide, 4- { [2-(isoquinolin- 1 -ylamino)quinazolin-6-yl] oxy } -N-methylpyridine-2-carbox-
amide, 4-({2-[(2-bromophenyl)ammo]qmnazolin-6-yl}oxy)-N-methylpyri
amide, 4-({2-[(2-ethylphenyl)amino]qmnazolin-6-yl}oxy)-N-methylpyridine-2-car^
amide, 4-( {2- [(3 -fluoro-2-methylphenyl)amino] quinazolm-6-yl } oxy)-N-methylpyridine-
5 2-carboxamide, N-methyl-4- [(2- { [2-(phenyloxy)phenyl] amino } quinazolin-6-yl)oxy] -
pyridine-2-carboxamide, N-methyl-4- { [2-(quinolin-2-ylamino)quinazolin-6-yl]oxy } -
pyridine-2-carboxamide, 4-( { 2- [(2,5 -dimethylphenyl) amino] quinazolin-6-yl} oxy)-N-
methylpyridine-2-carboxamide, N-methyl-4-[(2- { [5-methyl-2-(methyloxy)phenyl]-
amino } quinazolin-6-yl)oxy]pyridine-2-carboxamide, N-methyl-4- { [2-(pyridin-2-yl-
1 0 amino)qmnazolin-6-yl]oxy}pyridine-2-carboxamide, N-methyl-4-({2-[(2-morpholin-4-yl-
phenyl)amino] quinazoiin-6-yl} oxy)pyridine-2-carboxamide, N-methyl-
4-[(2-{[2-(methyloxy)-5-(trifluoromethyl)phenyl]amino}quinazolin-6-yl)oxy]pyri
carboxamide, 4-( {2- [(3 -fluorophenyl)amino] quinazolin-6-yl } oxy)-N-methylpyridine-
2-carboxamide, 4-( { 2- [(3 -chlorophenyl)amino] quinazolin-6-yl } oxy) -N-methylpyridine-
15 2-carboxamide, 4-({2-[(3-bromophenyl)amino]quinazolin-6-yl}oxy)-N-metliylpyridine-
2-carboxamide, 4- { [2-(2,3 -dihydro- 1 ,4-benzodioxin-6-ylamino)quinazolin-6-yl]oxy } -N-
methylpyridine-2-carboxamide, 4-[(2- { [3,5-bis(trifluoromethyl)phenyl]amino} -
quinazolin-6-yl)oxy]-N-methylpyridine-2-carboxamide, 4- [(2- { [3-chloro-4-(methyloxy)-
phenyl] amino } quinazolin-6-yl)oxy] -N-methylpyridine-2-carboxamide, N-methyl -4-
20 [(2- { [3 -(methylthio)phenyl] amino } quinazolin-6-yl)oxy]pyridine-2-carboxamide, N-
methyl-4-{ [2-(pyridin-3 -ylamino)quinazolin-6-yl]oxy }pyridine-2-carboxamide, N-
methyl-4- { [2-( { 3 - [(phenylmethyl)oxy]phenyl } amino)quinazolin-6-yl] oxy} pyridine-
2-carboxamide, 4- { [2-( 1 , 1 '-biphenyl-3-ylamino)quinazolin-6-yl]oxy} -N-methylpyridine-
2-carboxamide, N-methyl-4-{[2-({3-[(trifluoromethyl)oxy]phenyl}amino)quinazolin-6-
25 yl]oxy}pyridine-2-carboxamide, 4-({2-[(3-ethynylphenyl)amino]quinazolin-6-yl}oxy)-N-
methylpyridine-2-carboxamide, 4-( { 2- [(3 ,4-difluorophenyl)amino] quinazolin-6-yl } oxy)-
N-methylpyridine-2-carboxamide, 4-( {2- [(3 ,4-dimethylphenyl)amino] quinazolin-6-yl} -
oxy)-N-methylpyridine-2-carboxamide, N-methyl-4-({2-[(4-piperidin-l-ylphenyl)-
amino]quinazolin-6-yl}oxy)pyridine-2-carboxamide, N-methyl-4-[(2-{[4-(methyloxy)-
3 0 phenyl] amino } quinazolin-6-yl)oxy]pyridine-2-caxboxamide, 4-( { 2- [(4-ethylphenyl) -
amino]quinazolin-6-yl}oxy)-N-methylpyridine-2-carboxamide, 4-[(2-{[4-(butyloxy)-
phenyl] amino } quinazolin-6-yl)oxy] -N-methylpyridine-2-carboxamide, N-methyl-
4- [(2- { [4-( 1 -methylethyl)phenyl] amino } quinazolin-6-yl)oxy]pyridine-2-carboxamide,
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4- [(2- { [5 -chloro-2-(methyloxy)phenyl] amino } quinazolin-6-yl)oxy] -N-methylpyridine-
2-carboxamide, 4-[(2- { [5-cyclohexyl-2-(methyloxy)phenyl]ammo}quinazolin-6-yl)oxy]-
N-methylpyridine-2-carboxamide, N-methyl-4-( {2- [(4-methyl- 1 , 1 '-biphenyl-3 -yl)amino] -
qmnazolin-6-yl } oxy)pyridine-2-carboxamide, 4- { [2-(2 ,3 -dihydro- 1 H-mden-5 -ylamino)-
5 quinazolin-6-yl]oxy } -N-methylpyridine-2-carboxamide, 4- { [2-(l , 1 -biphenyl-4-ylamino)-
quinazolm-6-yl]oxy}-N-methylpyridine-2-carboxamide, 4-({2-[(4-fluorophenyl)amino]-
quinazolin-6-yl}oxy)-N-methylpyridine-2-carboxamide5 4-({2-[(2,3-difluorophenyl)-
amino]qmnazolin-6-yl}oxy)-N-methylpyridine-2-carboxamide, 4-({2-[(2,2-difluoro-
1 ,3 -benzodioxol-5 -yl)amino] quinazolin-6-yl } oxy)-N-methylpyridine-2-carboxamide5
10 4- { [2-(9H-fluoren-2-ylamino)quinazolin-6-yl]oxy } -N-methylpyridine-2-carboxamide,
4-( { 2- [(3 -cyclohexylphenyl) amino] quinazolin-6-yl } oxy)-N-methylpyridiiie-2-carbox-
amide, N-methyl-4- [(2- { [3 -( 1 -methylethyl)phenyl] amino } quinazolin-6-yl)oxy]pyridine-
2-carboxamide, 4-({2-[(4-bromophenyl)amino]quinazolin-6-yl}oxy)-N-[3-(2-oxo-
pyrrolidin- 1 -yl)propyl]pyridine-2-carboxamide, 4-({2-[(4-bromophenyl)amino]-
1 5 quinazolin-6-yl } oxy)-N-(2-hydroxy ethyl)pyridine-2-carboxamide, 4-( {2- [(4-bromo-
phenyl)amino] quinazolin-6-yl } oxy)-N- [3 -( 1 H-imidazol- 1 -yl)propyl]pyridine-2-carbox-
amide, 4-({2-[(4-bromophenyl)amino]quinazolin-6-yl}oxy)-N-[3-(methylox30pi'opyl]-
P3Tidine-2-carboxamide5 4-({2-[(4-bromophenyl)amino]quinazolin-6-yl}oxy)-N-
(2-piperidin- 1 -ylethyl)pyridine-2-carboxamide, 4-({2-[(4-bromophenyl)amino]-
20 quinazolin-6-yl}oxy)-N-propylpyridine-2-carboxamide5 4-({2-[(4-bromophenyl)amino]-
qmnazolin-6-yl} oxy)-N- [2-(dimethylamino)ethyl]pyridine-2-carboxamide5 N-methyl-
4-{[2-({3 - [(trifluoromethyl)thio] phenyl } amino)quinazolin-6 -yl] oxy } pyridine-2-carbox-
amide, 4-({2-[(4-chloro-2-£Iuorophenyl)amino]quinazolin-6-yl}oxy)-N-methylpyridine-
2-carboxamide, 4-({2-[(4-chloro-3-methylphenyl)amino]quinazolin-6-yl}oxy)-N-methyl-
25 p5n:idine-2-carboxamide, 4-({2-[(4-butylphenyl)amino]quinazolin-6-yl}oxy)-N-methyl-
pyridine-2-carboxamide, (4- {2- [(4-bromo-3 -methylphenyl)amino] (6-quiiiolyloxy) }-(2-
pyridyl))-N-methylcarboxamide, and N-methyl-4- [(2- { [3 -( 1 -methy lethyl)plienyl] -
amino} quinolin-6-yl)oxy]pyridine-2-carboxamide5 and other representative compounds
set forth in the Examples.
30 In other aspects, the present invention relates to the processes for preparing the
compoimds of Formulas I- VIII and to the synthetic intermediates useful in such
processes.
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The compoimds of the invention comprise asymmetrically substituted carbon
atoms. Such asymmetrically substituted carbon atoms can result in the compounds of the
invention comprising mixtures of stereoisomers at a particular asymmetrically substituted
carbon atom or a single stereoisomer. As a result, racemic mixtures, mixtures of
^ 5 diastereomers, as well as single diastereomers of the compounds of the invention are
included in the present invention. The terms "S" and "R" configuration, as used herein,
are as defined by the lUP AC 1 974 RECOMMENDATIONS FOR Section E, Fundamental
Stereochemistry, Pure Appl Chem, 45:13-30 (1976). The terms a and p are employed
for ring positions of cyclic compounds. The a-side of the reference plane is that side on
10 which the preferred substituent lies at the lower numbered position. Those substituents
lying on the opposite side of the reference plane are assigned [3 descriptor. It should be
noted that this usage differs from that for cyclic stereoparents, in which "a" means
"below the plane" and denotes absolute config\iration. The terms a and P configxaration,
as used herein, are as defined by the Chemical Abstracts Index Guide-Appendix IV
15 (1987) paragraph 203.
The present invention also relates to the processes for preparing the compounds of
the invention and to the synthetic intermediates useful in such processes, as described in
detail below.
Synthetic Methods
20 Compounds of the invention containing a quinazoline or quinoline core may be
prepared using a nxamber of methods familiar to one of skill in the art. In one method,
compotmds of the invention may be produced from the intermediate 2-chloro-6-
methoxyquineizoline 8, which may be obtained as described in the following scheme and
in Example 1 , below.
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K2CO3
Mel/DMF
Glycol, tosic acid
Toluene, Dean-Stark
OMe
O2N
EtOH, Pt02. H2
H2N
OMe
EtOCOCl / THF
EtOOCHN^^^
OMe
Cone. HCI
OMe i^Hs at 0"C
Bomb/130"C.DIV1F HO
lOeqPOCls
95-1 OO'C, 2h
neutralise with NaaCOa to pH 10
Extract with EtOAc
8
In this scheme 5-hydroxy-2-nitrobenzaldehyde 1 is reacted in DMF with
iodomethane and potassium carbonate to yield 5-methoxy-2-nitrobenzaldehyde 2. The
5 methoxybenzaldehyde is heated with p-toluene sulfonic acid monohydrate (catalytic
amount) in toluene to obtain the dioxane derivative 3, which is hydrogenated to give 2-
(13-dioxolan-2yl)-4-methoxyphenylamine 4. Following conversion to the
ethoxycarboxamide 5 and then to the formyl carboxamide 6, 6-methoxyquinazohn-2-ol 7
is obtained by ring closure with ammonia. Reaction with phosphoms oxychloride then
10 yields the desired 2-chloro-6-methoxyquinazoline intermediate 8.
Scheme A:
Br
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Referring to reaction scheme A, above, representative compounds of the invention
may be obtained by reacting 6-methoxyquinazolin-2-ol 8 and with an arylamine, such as
4-bromoamline, to obtain the corresponding arylmethoxyquinazoline 9, which may be
heated to obtain tlie corresponding alcohol 10. The desired substituent, such as
5 4-chloro(2"pyridyl)-N-methylcarboxamide, is then added to the alcohol group to obtain
the desired compound of the invention, in this case 4-{2-[(4-bromophenyl)amino]-
quinazolin-6-yloxy } -(2-pyridyl)-N-methylcarboxamide 1 1 .
□HMDS, K2CO3 O
^ ^ ^ n 11 mCPBA
170X, 480Sec - 14
90°C, 2 days
In the alternate reaction Scheme B, above, the 2"Chloro-6-methoxyquinazoline 8 is
reacted with sodium thiomethoxide in ethanol, dry methylene chloride, ethane thiol and
aluminum chloride to obtain the 2-methylthioquinazolin-6-ol 13. The desired substituent,
in this case 4-chloro(2-pyridyl)-N-methylcarboxamide, is added to the alcohol group to
15 obtain the corresponding substituted methylthioquinazoline 14. Treatment with
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3-cliloroperoxybenzoic acid in acetic acid results in the corresponding sulfonyl 15, which
is replaced by a desired substituent, in this case 2-naphthylaniline, to obtain the desired
compound of the invention, in this case N-methyl-4-{[2-(naphthalen"2-yIamino)-
quinazolin-6-yl]oxy}pyridine-2-carboxamide.
Quinoline compounds of the invention can be similarly synthesized, such as in the
following reaction Scheme C:
170X/360sec
As set forth in reaction Scheme C, quinoline2,6-dioI is chlorinated with POCI3 to
obtain 2-chloroquinolin-6-ol, which is reacted with a desired amine substituent, in this
case 4-bromo-3-methylaniline, and to obtain the amine substituted quinolinol. A mixture
of the alcohol and potassium bis(trimethylsilyl)amide in dimethylformamide is reacted
with a desired substituent at the alcohol group, in tlais case dimethylformamide, to obtain
the desire product, in this case (4-{2-[(4-bromo-3-methylphenyl)amino](6-
quinolyloxy) } (2-pyridyl) )-N-methylcarboxamide .
Compoimds of the invention wherein Y ^ O or S may generally be prepared as
shown in examples 1-92 below. Compounds containing Y = C may generally be
prepared as described in WO 03/031458, Compounds having Y = N may generally be
prepared by treating hydroxy-substituted quinolinyl, isoquinolinyl, or quinazolinyl
compounds with triflic anhydride followed by the appropriate aryl or heteroaryl amines
under Pd catalyzed conditions (Old, D.W.; Wolfe, J.P.; Buchwald, S. L. X Am, Chem,
Soc, 1998, 120, 9722-9723).
Various other compounds of the invention can be made by treating an
appropriately functionalized heteroaryl or aryl acid (-A2-COOH) with sodium azide or
diphenylphosphoryl azide under Schmidt/Curtius rearrangement conditions to form the
corresponding heteroarylisocyanate (-A2-N=C=0) intermediates. These isocyanates need
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not be isolated and may be readily converted via known procedures to amines, amides,
thioamides, carbamates, thiocarbamates, ureas, and thioixreas.
The compounds of the invention are useful in vitro or in vivo in inhibiting the
growth of cancer cells. The compounds may be used alone or in compositions together
5 with a pharrnaceutically acceptable carrier or excipient. Suitable phantnaceutically
acceptable carriers or excipients include, for example, processing agents and drug
delivery modifiers and enhancers, such as, for example, calcium phosphate, magnesium
stearate, talc, monosaccharides, disaccharides, starch, gelatin, cellulose, methyl cellulose,
sodium carboxymethyl cellulose, dextrose, hydroxypropyl-P-cyclodextrin, polyvinyl-
10 pyrroUdinone, low melting waxes, ion exchange resins, and the like, as well as
combinations of any two or more thereof. Other suitable pharrnaceutically acceptable
excipients are described in "Remington's Pharmaceutical Sciences," Mack Pub. Co., New
Jersey (1991), incorporated herein by reference.
Effective amounts of the compounds of the invention generally include any
1 5 amount sufficient to detectably inhibit Raf activity by any of the assays described herein,
by other Raf kinase activity assays known to those having ordinary skill in the art or by
detecting an inhibition or alleviation of symptoms of cancer.
The amoimt of active ingredient that may be combined with the carrier materials
to produce a single dosage form will vary depending upon the host treated and the
20 particular mode of administration. It will be understood, however, that the specific dose
level for any particular patient will depend upon a variety of factors including the activity
of the specific compoimd employed, the age, body weight, general health, sex, diet, time
of administration, route of administration, rate of excretion, drug combination, and the
severity of the particular disease imdergoing therapy. The therapeutically effective
25 amoxmt for a given situation can be readily determined by routine experimentation and is
within the skill and judgment of the ordinary clinician.
For pixrposes of the present invention, a therapeutically effective dose will
generally be a total daily dose administered to a host in single or divided doses may be in
amounts, for example, of firom 0.001 to lOOOmg/kg body weight daily and more
30 preferred jfrom 1.0 to 30mg/kg body weight daily. Dosage unit compositions may
contain such amounts of submultiples thereof to make up the daily dose.
The compotmds of the present invention may be administered orally, parenterally,
sublingually, by aerosolization or inhalation spray, rectally, or topically in dosage unit
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formulations containing conventional nontoxic pharmaceutically acceptable carriers,
adjuvants, and vehicles as desired. Topical administration may also involve the use of
transdermal administration such as transdermal patches or ionophoresis devices. The
term parenteral as used herein includes subcutaneous injections, intravenous,
5 intramuscxilar, intrastemal injection, or infusion techniques.
Injectable preparations, for example, sterile injectable aqueous or oleaginous
suspensions may be formulated according to the known art using suitable dispersing or
wetting agents and suspending agents. The sterile injectable preparation may also be a
sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or
10 solvent, for example, as a solution in 1,3 -propanediol. Among the acceptable vehicles
and solvents that may be employed are water, Ringer^s solution, and isotonic sodium
chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent
or suspending medium. For this purpose any bland fixed oil may be employed including
synthetic mono- or di-glycerides. In addition, fatty acids such as oleic acid find use in the
1 5 preparation of inj ectables .
Suppositories for rectal administration of the drug can be prepared by mixing the
dmg with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols,
which are solid at ordinary temperatures but liquid at the rectal temperature and will
therefore melt in the rectum and release the drug.
20 Solid dosage forms for oral administration may include capsules, tablets, pills,
powders, and granules. In such solid dosage forms, the active compound may be
admixed with at least one inert diluent such as sucrose lactose or starch- Such dosage
forms may also comprise, as is normal practice, additional substances other than inert
diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules,
25 tablets, and pills, the dosage forms may also comprise buffering agents. Tablets and pills
can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration may include phannaceutically
acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents
commonly used in the art, such as water. Such compositions may also comprise
30 adjuvants, such as wetting agents, emulsifying and suspending agents, cyclodextrins, and
sweetening, flavoring, and perfuming agents.
The compounds of the present invention can also be administered in the form of
liposomes. As is known in the art, liposomes are generally derived from phospholipids or
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other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid
crystals that are dispersed in an aqueous medium. Any non-toxic, physiologically
acceptable and metabolizable lipid capable of forming liposomes can be used. The
present compositions in liposome form can contain, in addition to a compound of the
5 present invention, stabilizers, preservatives, excipients, and the like. The preferred lipids
are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
Methods to form liposomes are known in the art. See, for example, Prescott, Ed.,
Methods in Cell Biology^ Volume XIV, Academic Press, New York, N.W., p. 33 etseq.
(1976).
10 While the compounds of the invention can be administered as the sole active
pharmaceutical agent, they can also be used in combination with one or more other agents
used in the treatment of cancer. Representative agents useful in combination with the
compoxmds of the invention for the treatment of cancer include, for example, irinotecan,
topotecan, gemcitabine, 5-fluorouracil, leucovorin carboplatin, cisplatin, taxanes,
15 tezacitabine, cyclophosphamide, vinca alkaloids, imatinib (Gleevec), anthracyclines,
rituximab, trastuzumab, dacarbazine, aldesleukin, capecitabine, and Iressa (gefitinib), as
well as other cancer chemotherapeutic agents.
The above compounds to be employed in combination with the compounds of the
invention will be used in therapeutic amomits as indicated in the Physicians* Desk
20 Reference (PDR) 47th Edition (1993), which is incorporated herein by reference, or such
therapeutically useful amounts as would be known to one of ordinary skill in the art.
The compounds of the invention and the other anticancer agents can be
administered at the recommended maximum clinical dosage or at lower doses. Dosage
levels of the active compounds in the compositions of the invention may be varied so as
25 to obtain a desired therapeutic response depending on the route of administration, severity
of the disease and the response of the patient. The combination can be administered as
separate compositions or as a single dosage form containing both agents. When
administered as a combination, the therapeutic agents can be formulated as separate
compositions, which are given at the same time or different times, or the therapeutic
30 agents, can be given as a single composition.
Antiestrogens, such as tamoxifen, inhibit breast cancer growth through induction
of cell cycle arrest, that requires the action of the cell cycle inhibitor p27Kip. Recently, it
has been shown that activation of the Ras-Raf-MAP Kinase pathway alters the
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phosphorylation status of p27Kip such that its inhibitory activity in arresting the cell
cycle is attenuated, thereby contributing to aatiestrogen resistance (Donovan et al, J. Biol.
Chem. 27^:40888, 2001). As reported by Donovan et al., inhibition of MAPK signaling
through treatment with MEK inhibitor changed the phosphorylation status of p27 in
hormone refactory breast cancer cell lines and in so doing restored hormone sensitivity.
Accordingly, in one aspect, the compoxmds of formulas (I) - (V) may be used in the
treatment of hormone dependent cancers, such as breast and prostate cancers, to reverse
hormone resistance commonly seen in these cancers with conventional anticancer agents.
In hematological cancers, such as chronic myelogenous leukemia (CML),
chromosomal translocation is responsible for the constitutively activated BCR-ABl
tyrosine kinase. The afflicted patients are responsive to Gleevec, a small molecule
tyrosine kinase inhibitor, as a result of inhibition of Abl kinase activity. However, many
patients with advanced stage disease respond to Gleevec initially^ but then relapse later
due to resistance-conferring mutations in the Abl kinase domain. In viti^o studies have
demonstrated that BCR-Avl employs the Raf kinase pathway to elicit its effects. In
addition, inhibiting more than one kinase in the same pathway provides additional
protection against resistance-conferring mutations. Accordingly, in another aspect of the
invention, the compoimds of formulas (I)-(VIII) are used in combination with at least one
additional agent, such as Gleevec, in the treatment of hematological cancers, such as
chronic myelogenous leukemia (CML), to reverse or prevent resistance to the at least one
additional agent.
The present invention will be imderstood more readily by reference to the
following examples, which are provided by way of illustration and are not intended to be
limiting of the present invention.
Representative side chains for use in the compounds of the following examples
may generally be prepared in accordance with the following procedures:
Example 1
Svnthesis of r4-l2-rr4-bromophenvnaminQlquinazolin-6-vloxv>-
(2-pvridvI)VN-methvlcarboxamide
o
H
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The compound (4-{2-[(4-bromophenyl)amino]quinazolm-6-yloxy}-(2-pyridyl))-
N-methylcarboxamide was synthesized as follows:
Step 1. Synthesis of 5-methoxy-2-nitrobenzaldehyde 2:
A mixture containing 5-hydroxy-2-nitrobenzaldehyde (Icq) in DMF with
5 iodomethane (l.leq) and potassium carbonate (leq) was stirred at room temperatixre for
16 hours. The resulting mixture was concentrated and partitioned between ethyl acetate
and water. The organic layer was washed with brine and dried and concentrated to afford
5-methoxy-2-nitrobenzaldehyde in quantitative yield.
MS:MH+- 182.
10 Step 2. Synthesis of 2-(l 3 -dioxolan-2"ylV4-methoxy-l -nitrobenzene 3
The mixture 5-methoxy-2-nitrobenzaldehyde (leq), etliylene glycol (1.4eq) and p-
toluene sulfonic acid monohydrate (catalytic amount) in toluene was heated to reflux with
a Dean-Stark apparatus for 16 hours. The mixture was then concentrated and passed
through a plug of silica to give 2-(13-dioxolan-2-yl)-4-methoxy-l -nitrobenzene in 85-
15 90% yield.
MS:MH+ = 226.
Step 3. Synthesis of 2-(L3-dioxolan-2-yl)"4-methoxyphenylamine 4
A solution of 2-(l,3-dioxolan-2-yl)-4-methoxy-l -nitrobenzene (leq) in ethyl
acetate was treated with sodium acetate (O.OSeq) and platinum oxide (0.06eq) and
20 hydrogenated in a Parr apparatus at 50psi for 16 hours. The reaction mixture was filtered
and the filtrate was concentrated to give 2-(l53-dioxolan-2yl)-4-methoxyphenylamine in
quantitative yield.
MS:MH+- 196.
Step 4. Synthesis of N-(2-( 1 ,3 -dioxolan-2-yl)-4-methoxyphenyl)ethoxy-
25 carboxamide 5
Ethyl chloroformate (1.2 eq) was added to 2-(13-dioxolan-2-yl)-4-
methoxyphenylamine (leq) and triethyl amine (1.2 eq) in THF at 0 °C. The reaction was
completed instantaneously. The mixture was concentrated and partitioned between ethyl
acetate and water. The organic layer was washed with brine and dried and concentrated
30 to give N-(2-(l,3-dioxolan-2-yl)-4-metlioxyphenyl) ethoxycarboxamide as a yellow solid
in quantitative yield.
MS:MH+ =268.
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Step 5. Synthesis of Ethoxv-N"(2-formYl-4-methoxvphenvl)carboxamide 6
N-(2-(13-dioxolan-2-yl)-4-methoxyphenyl)ethoxycarboxainide was dissolved in
acetone and to it was added hydrochloric acid. The mixture was stirred at room
temperature for 4 hours. The solvent was removed in vacuo to give ethoxy-N-(2-formyl-
4-methoxyphenyl)carboxamide quantitatively.
MS:MH+ =224
Step 6. Synthesis of 6-methoxvquinazolin-2"Ol 7
Ammonia was bubbled into ethanol cooled to dry ice bath temperature for 1 hour.
Ethoxy-N-(2-formyl-4-methoxyphenyl)carboxamide was added and the resultant solution
was heated to 130 °C in an autoclave for 16 hours. The brown solution was treated with
charcoal, filtered and the filtrate was concentrated. A yellow was subjected to
chromatography to give 6-methoxyquinazolin-2-ol.
MS:MH+ =177
Step 7. Synthesis of 2-chloro-6-methoxyquinazoline 8
6-methoxyquinazolin-2-ol (leq) and phosphorus oxychloride (2-lOeq) was
refluxed for 2 hours. The reaction mixture was concentrated and neutralized with
sodium carbonate, which was then filtered off. The concentrate was partitioned between
ethyl acetate and water. The organic layer was then washed with brine dried and
concentrated. The crude was subjected to column chromatography (10%Acetone in
hexane) to afford 2-chloro-6-methoxyquinazoline as a beige color solid in 90% yield.
MS: MHH- = 195.
Step 8. Synthesis of f4-bromophenyiy6-methoxyquinazolin"2-yl) amine 9
2-chloro-6-methoxyquinazoline (leq) and 4-bromoaniline (2eq) in ethanol was
heated at 80 °C for 1 6 h. The mixture was concentrated and passed through a plug of
silica to yield (4-bromophenyl)(6-methoxyquinazolin-2-yl)amine.
MS:MH+ =330.
Step 9. Synthesis of 2"r('4-bromophenyl)amino]quinazolin-6-ol 10
(4-bromophenyl)(6-methoxyquinazolin-2-yl)amine in HBr was heated at 100 °C
for 16 hours. The reaction mixture was concentrated and purified on preparative
chromatography. Lyophillization yielded 2-[(4-bromophenyl)amino]quinazolin-6-oL
MS: MH+ =316.
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Step 1 0, Synthesis of ^4- j2-^f4-bromophenyDamillo1qu^nazol^n-6-vloxvl-(2-
PYridyl)VN-methYlcarboxamide
The mixtiore containing 2-[(4-bromophenyl)amino]quinazoHn-6-ol (leq),
potassiumbis(trimethylsilyl)amide (4eq) was stirred in dimethylformamide for 10 min at
5 room temperature. To this mixture was added (4-chloro(2-pyridyl)-N-
methylcarboxamide (leq) and Potassium carbonate (1.2eq) and micro waved for 6 mins at
170 °C. The reaction mixture was then concentrated and partitioned between ethyl
acetate and water. The organic layer was separated and washed with brine^ dried, filtered
and concentrated. Purification on preparative chromatography yielded 4-{2-[(4-
1 0 bromophenyl)ainino]quinazolin-6-yloxy } -(2-pyridyl)-N-methylcarboxamide in 70-75%
yield.
MS: MH+ =450.
Examples 2-108
The compounds shown in the following Table 1 (Examples 2- 1 6) were prepared
15 by following the procedure described for Example 1 .
Table 1
Example
Structure
Name
MH+
2
O r-\ Chiral
H
4-({2-[(4-bromophenyl)amino] -
quinazolin-6-yl } oxy)-N- [(3 R)-
pyrrolidin-3-yl]pyTidine-2-
carboxamide
506.4
3
CH3
4-({2-[(4-bromophenyl)(methyl)-
amino] quinazolin-6-yl } oxy)-N-
methylpyridine-2-carboxamide
465.3
4
4-[(2-{ [4-bromo-3-(trifluoro-
methyl)phenyl] amino } quinazolin-
6-yl)oxy] -N-methylpyridine-2-
carboxamide
519.3
5
H
N-methyl-4-( { 2- [(4-methylphenyl)-
amino]quinazolin-6-yl} oxy)-
pyridine-2-carboxamide
386.4
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Example
Structure
Name
MH+
6
o
H
N-methyl-4-[(2-{[4"
(phenyloxy)phenyl] amino } quinazo
lin-6-yl)oxy]pyridine-2-
carboxamide
464.5
7
O
4-({2-[(4-bromo-3-
chlorophenyDamino] qmnazolin-6-
yl } oxy)-N-methylpyridine'-2-
carboxamide
485.7
8
0
H
4-( { 2-[(4-bromo-3 -fluorophenyl)-
ammo]quinazolin-6-yl} oxy)-N-
methylpyridine-2-carboxamide
469.3
9
CH3
N-methyl-4-( {2-[methyl(phenyl)-
amino] qioi nazolin-6-yl } oxy) -
pyridine-2-carboxamide
386.4
1
10
CH,
4-( {2-[(4-chlorophenyl)(methyl)-
amino] quinazoliii-6-yl} oxy)-N-
iiic Liiy ip y 1 1 ciiiic-^ -cdxu u xaiiiicie
420.9
11
CH3
N-methyl-4- { [2-(methyl {4-
[(trifluoromethyl)oxy]phenyl} amin
o^Quinazolin- 6-vl1 oxvi DvridirLC-2-
carboxamide
470.4
12
CH3
4-({2-[(4-
fluorophenyl)(methyl)amino]quina
zoun-o-yi j- oxy J-JN -metnyipyriame-
2-carboxamide
404.4
13
0
CH3
N-methyl-4-( { 2- [methyl(4-methyl-
phenyl)ammolquinazolin-6-yl} -
oxy)pyridine-2-carboxamide
400.5
14
0
H
4-({2-[(4-cyclohexylphenyl)-
amino J quuiazoim-o-yi j- oxy j-rs -
methylpyridine-2-carboxamide
454.5
15
H
4-( {2- [(4-chlorophenyl)amino] -
quinazoIin-6-yl} oxy)-N-methyl-
pyridine-2-carboxamide
40618
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Example 16
Synthesis of N-methYl-4- 1 r2-(naphthalen-2-vlaminQ)-
qmnazolin-6-vll oxv> p vridme-2-carboxaiiiide
.J-
H
N
N
H
.CH3
5
Step 1 :
Synthesis of N-methyl[4-(2-methyIthioquinazolin-6-yloxy)(2-
pyridyl)]carboxainide 14:
The mixture of 2-chloro-6-methoxyquinazoline (leq) and sodixjmthiomethoxide
(2eq) in ethanol (0.5M) was refluxed for 3 hours. The reaction was cooled down to room
10 temperature and evaporated. The mixture was taken in ethyl acetate and washed with
water and brine, dried in sodium sulfate and concentrated. The resulting crude was
treated with dry methylene chloride and ethane thiol (5eq) was added to it at room
temperature. Aluminium chloride (5eq) was added carefully at 0°C. The reaction was
warmed to room temperature and stirred vigorously over night. The reaction was diluted
15 with methylene chloride and saturated Rochelles's salt solution was added and stirred for
about 3 hours until 2 layers separated. The organic layer was separated, washed with
RochcUe's salt solution (2X), followed by water and brine, dried and evaporated. The
crude 2-methylthioquinazolin-6-ol (leq) was taken in DMF (0.5M) and
Potassiumbis(trimethylsilyl)amide (2eq) was added and stirred for 10 min at room
20 temperature. 4-chloro(2-pyridyl)-N-methylcarboxamide (l.leq) was added followed by
potassium carbonate (leq) and stirred at SS-PC'C for l6hours. The mixture was diluted
with ethyl acetate, washed with water and brine, dried and evaporated. The crude was
subjected to column chromatography (4:1 Hexanes in ethyl acetate followed by 2:1 and
1:1 Hexanes in ethyl acetate) to afford the product in 75-85% yield.
25 Step 2. Synthesis of N-methyl[4-(2-methylsulfonylquinazolin-6-yloxy)(2-
pyridyl)]carboxainide 15:
The solution of N-methyl[4-(2-methylthioquinazolin-6-yloxy)(2-pyridyl)]-
carboxamide in methylene chloride (0.5M) was treated with acetic acid (8-10%) and
stirred for 5 min at room temperature. 3-chloroperoxybenzoic acid (2eq) and after 2hours
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another (leq) was added and stirred for 3 hours at room temperature. The reaction was
diluted with methylene chloride and neutralized to pH8-9 witli saturated sodium
bicarbonate very carefully. The organic layer was separated, washed with water and
brine to afford the product. The crude was subjected to column chromatography (1:1
5 hexanes in ethyl acetate) to afford the product quantitatively.
Step 3. Synthesis of N-methyl-4-{[2-(naphthalen-2-ylamino)-quinazolin-6-
yl] oxy }pyridine-2-carboxamide
N-methyl[4-(2-methylsulfonylquinazolin-6-yloxy)(2-pyridyl)]carboxamide 15
(leq) was treated v^ith 2-naphthylamUne (2eq) in acetonitrile (IM) and heated at 80-
0 85°C. The mixture was evaporated and purified on preparative chromatography to give
the product.
Each of the Examples 17-119 shown in the following Table 2 were synthesized
according to the procedure described in Example 109:
15 Table 2
Example
Structure
Name
MH+
17
H
N-methyl-4-{ [2-({4-[(trifluoro-
methyl)oxy]phenyl } amino) -
quinazolin-6-yl] oxy }pyridine-2-
carboxamide
456.4
18
H
N-methyl-4-[(2-{[4-
(trifluoromethyl)phenyl] amino } qui
nazolin-6-yl)oxy]pyridine-2-
carboxamide
440.4
19
F^F ^
4-[(2-{[2-fluoro-5-
(trifluoromethyl)phenyl] amino } qui
nazolin-6-yl)oxy] -N-
methylpyridine-2-carboxamide
458.4
20
H
N-methyl-4-[(2-{[3-
(trifluoromethyl)pheny 1] amino } qui
nazolin-6-yl)oxy]pyridine-2-
carboxamide
440.4
21
GHg 0
H
4-C{2-[(4-bromo-3-
methylphenyl)amino]quina2;olin-6-
yl } oxy)-N-methylpyridine-2-
carboxamide
465,3
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Example
Structure
Name
MH+
22
4-[(2-{[4-fluoro-3-
(trifluoromethyl)phenyl] amino } qui
nazolin-6-yl)oxy] -N-
methylpyridine-2-carboxamide
458.4
23
N-methyl-4-[(2-{[4-
(methylthio)phenyl] amino } quinazo
lin-6-yl)oxy]p)Tidine-2--
carboxamide
418.5
24
N-methyl-4-{[2-({4-
[(phenylmethyl)oxy]phenyl} amino
)quinazolin-6-yl] oxy }pyridine-2-
carboxamide
478.5
25
N-methyl-4-( {2-[(4-morpholin-4-
ylphenyl)amino] quinazolin-6-
yl} Qxy)pyridine-2-carboxamide
457,5
26
4-( { 2- [(6-chloropyridin-3 -
yI)amino]quinazolin-6-yl} oxy)-N-
methylpyridine-2-carboxamide
407.8
27
4-[(2-{[4-chloro-3-
(trifluoromethyl)phenyl] amino } qui
nazolin-6-yl)oxy]-N-
methylpyridine-2-carboxamide
474.8
28
4-({2-[(3,5-
dichlorophenyl)amino]quinazolin-
6-yl } oxy)-N-methylpyridine-2-
carboxatnide
441.3
29
-CH,
N-methyl-4-[(2-{[6-
(methyloxy)pyridin-3 -
yl] amino } quinazolin-6-
yl)oxy] pyridme-2-carboxainide
403.4
30
N N
I
H
N-methyl-4-{[2-
(phenylamino)quinazolin-6-
yl] oxy}pyridine-2-carboxamide
372,4
31
4- { [2-(bicyclo [2 .2 . 1 ]hept-2-
ylamino)quinazolin-6-yl] oxy } -N-
methylpyridine-2-carboxamide
390,5
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Example
Structure
Name
MH+
32
o
1
H
4-{[2-
(cyclohexylamino)quina2;olin-6-
ylloxy} -N-methylpyridine-2-
carboxatnide
378.4
33
1
H
0
N-methyl-4-({2-
[(phenylmethyl)aminojqumazolin-
6-yl } oxy)pyridine-2-carboxainide
386.4
34
1
H
N-methyl-4-({2-[(2-
phenylethyl)amino]quinazolin-6-
yl } oxy)pyridine-2-carboxamide
1
H
4- [(2- { [(1 -ethylpyrrolidm-2-
yl)methyllamino } quinazolin-6-
yl)oxy] -N-methylpyridine-2-
carboxamide
407.5
36
Br H
0
4-[(2-{[2-bromo-4-(l-
methylethyl)phenyll amino } quinazo
lin-6-yl)oxy] -N-methylpyridine-2-
carboxamide
37
F H
4_({2-[(4-bromo-2-
fluorophenyl) amino] quinazolin-6-
yl } oxy)-N-methylpyridine-2-
carboxamide
469.3
Examples 38-90
Additional Compounds
Following the foregoing general procedures, the following additional compounds
5 were prepared:
Table 3
Example
Stmcture
Name
MH+
38
4-( {2-[(2,4-dichlorophenyl)amino]-
quinazolin-6-yl} oxy)-N-methyl-
p)Tidine-2-carboxamide
441.3
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Example
Structure
Name
MH+
,
39
o
4-{ [2"(isoqumolin- 1 -ylamino)-
qiiinazolin-6-yl]oxy } -N-methyl-
pyriame-2-carboxamiae
423 4
40
o
Br H
4-( { 2 - [(2'-bromophenyl)ainino] -
quinazoliti-6-yl} oxy)-N-methyl-
pyridme-2-carboxamide
451.3
41
4-({2- [(2-ethylphenyl)amino]-
qmnazolin-6-yl} oxy)-N-methyl~
pyridine-2-carboxamide
42
F J N N
CH3 H
4-({2-[(3-fluoro-2-
methy lphenyl)ainmo] quinazolin-6-
vl 1 oxvVN-rnethvlt)VTidinc-2-
carboxamide
404.4
43
N N
^--^^0 H
u
N-methyl-4-[(2- { [2-(pbeayloxy)-
phenyl] amino } quina2:olin-6 -
yl)oxy]pyridine-2-carboxamide
454.3
44
0
!
H
N-methyl-4- { [2-(qumolm-2-
vl amiiio^Quinazoliii-6-vll ox v \ -
pyridine-2-carboxamide
423.4
45
CH3 k
4-({2-[(2,5-dimethylphenyl)-
amino]quinazolin-6-yl}oxy)-N-
methylpyridine-2 -carboxamide
46
CH3 0
H3C'° "
N-methyl-4-[(2-{ [5-methyl-2-
(methyloxy)phexiyl] amino} -
qmnazolin-6-yl)oxy]pyridine-2-
carboxamide
416.5
47
N N N
1
H
N-methyl-4-{ [2'-(pyridin-2-
ylamino)quinazolin-6-yl] oxy } -
pyriame-z-carboxamiae
373.4
48
0'
N-methyl-4-({2-[(2-morpholin-4-
ylphenyl)amino] quinazolin-6-
yl} oxy)pyridine-2-carboxamide
457.5
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Example
Structure
Name
MH+
49
<
H
N-methyl-4-[(2- { [2-(niethyloxy)-5"
(trifluoromethyl)phenyl] amino } qm
nazolia-6-yl)oxy]pyridine-2-
carboxamide
4 /U.4
50
1
H
4-({2-[(3 -fluorophenyl)amino] -
qumeizolm-6 -yl } oxy)-N-mefhyl -
pyridine-2-carboxamide
390.4
51
CI o
1
H
4-({2- [(3-chloropherLyl)amino]-
cjumazoiiii-0"-yi / oxy j-rs -meiiiyi-
pyridine-2-carboxamide
406.8
52
Br O
1
H
4-( { 2- [(3 -bromophenyl) amino] -
quinazolin-6-yl } oxy )-N-methy 1-
pyridine-2-carboxamide
451 3
53
1
H
4-{[2-(23-dihydro-l,4-benzo-
dioxin-6-ylamino)qmnazolixi-6-
vlloxv^ -N-metlivlDvridine-2-
carboxamide
430.4
54
F
F f F
H
4- [(2- { [3 ,5-bis(trifluoromethyl)-
phenyl]amino } quinazolin-6-yl)-
oxyj -N -metuy ipy name- z -car D ox-
amide
508.4
55
CH3 CI 0
I
H
4- [(2- { [3-chloro-4-(methyloxy)-
phenyl] amino } quinazolin-6-yl)-
oxy] -N-methylpyridine-2 -
carboxamide
56
^^-s 0
N-methyl-4-[(2-{ [S^methylthio)-
phenyllamino } quinazolin-6-yl)-
oxy]pyridine-2-carboxamide
418.5
57
H
N-methy^4-{[2-(pyridin-3-yl-
amino)quinazolin-6-yl]oxy } -
pyridine-2-carboxamide
373.4
58
1
H
N-methyl^4- { [2-( { 3 -[(phenyl-
metiiyl)oxy]phenyl } arQino)qiiinazo
lin-6-yl] oxy } pyridine-2 -
carboxamide
478.5
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Example
Structure
Name
MH+
59
0
4- { [2-( 1 , r -biphenyl-3 -ylamino)-
quuicizoiiii-o-yijoxy -in -mexnyi-
pyridine-2"Carboxamide
448.5
60
o
1
H
N-methyl-4-{ [2"({3-[(trifluoro-
qiimazolin-6-yl]oxy}pyridine-2-
carboxamide
456.4
61
o
HC^ ^
H
4-({2-[(3-ethynylphenyl)amino]-
QUiiiaZ,oiiii'"D"yi J 0/i.y J -mciiiy 1-
pyridine-2-carboxamide
396.4
62
0
H
4-({2- [(3,4-difluorophenyI)amino]-
quinazolin-6-yl } oxy)-N-methyl-
pyridine-2-carboxamide
y1 AO A
63
p
4-( {2-[(3,4-dimethylphenyl)-
amino] qmnaz;olin-6-yl } oxy)-N-
methylpyridme-2-carboxamide
4UVJ.D
64
I
H
N-methyl-4-( {2- [(4-piperidin- 1 -
ylpheriyl)aminolquinazolin-6-yl} -
oxy)pyridine-2-carboxamide
/I c ^
65
H
N-methyl-4-[(2-{ [4-(methyloxy)-
pheny 1] amino } quina2:olm-6-yl)-
oxy]pyridine-2-carboxainide
40? 4
66
CH3 0
H
4-({2" [(4-ethylphenyl)ainino]-
qiiina2oiin-6-yl } oxy)-N-methyl-
pyridine-2-carboxainide
400.5
67
1 ^
1
H
4-[(2 - { [4-(butyloxy)phenyl] -
amino } quinazolin-6-yl)oxy] -N-
methylpyridine-2-caxboxamide
444.5
68
CH3 0
H
N-methyl-4-[(2- { [4-(l -methyl-
ethyl)plienyl] amino } quinazolin-6-
yl)oxy]pyridine-2-carboxamide
414.5
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Example
Structure
Name
MH+
69
HgC
4-[(2- { [5-chloro-2-(methyloxy)-
phenyl] amino } quinazolin-6-yl)-
oxy] -N-methylpyridine-2-
carboxamidc
436.9
70
4"[(2- { [5-cyclohexyl-2-(methyl-
oxy)phenyl] amino } qmnazolin-6-
yl)oxy] -N-methylpyridine-2-
carboxamide
484.6
71
9
CH3 H
N-methyl-4-({2- [(4-methyl- 1,1'-
biphenyl-3 -yl)amino]quina2;olin-6-
yl} oxy)pyridine-2-carboxamide
462.5
72
4- { [2-(2,3 "dihy dro" 1 H-mden-5 -
y lammo jqumazo iin- o -y i j oxy ) - in -
methylpyridine-2 -carboxamide
412.5
73
I
H
4- { [2-(l , 1 -biphenyl-4-ylainino)-
quinazolin-6-yl] oxy} -N-methyl-
pyridine-2-carboxamide
448.5
74
0
1
H
4-({2- [(4-fluoroplienyl)amino]""
qumazolm-o-yl } oxyj-N -metnyl-
pyridine-2-carboxamide
390.4
75
0
F H
4-( { 2- [(2 ,3 -difluoropheny l)amino] -
quinazolin-6-yl} oxy)-N-methyl"
pyridine-2-carboxamide
408.4
76
F
1
H
4-( { 2- [(2,2-difluoro- 1 ,3 -benzo-
dioxol-5 -vDaminol auinazolin-6-
yl} oxy)-N-methylpyridine-2-
carboxamide
452.4
77
0
4- { [2-(9H-fluoren-2-ylainino)-
quinazolin-6-yl]oxy}-N-methyl-
pyridine-2-carboxainide
460.5
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Example
Structure
Name
MH+
78
l'^ o
r
H
4-({2-[(3 -cyclohexylphenyl)-
amino]qmiiazolin-6-yl} oxy)-N-
methylpy ridine-2 -carboxamide
454.5
79
H
N-methyl-4-[(2-{ [3 -(1 -methyl-
ethyl)phenyl]amino} quinazolin-6-
yl)oKy] pyridine-2 - carboxamide
414.3
80
O
4-( {2- [(4-bromophenyl) amino] -
quinazolin-6-yl} oxy)-N-r3 -(2-
oxopyrrolidin-1 -yl)propyl]-
pyridine-2-carboxamide
562.4
81
o
1 .
H
4-( {2- [(4-bromophenyl) amino] -
quina2olin-6-yl } oxy)-N-(2-
hydroxyethyl)pyridine-2-
carboxamide
481.3
82
H
4-( {2- [(4-bromophenyl)amino] -
qiiinazolin-6-yl} oxy)-N-[3 -( 1 H-
imidazol- 1 -yl)propyl]pyridine-2-
carboxamide
545.4
83
0
H CH3
4-( (2- [(4-bromophenyl) amino] -
quinazolin-6-yl} oxy)-N-[3 -
(methyloxy)propyl]pyridine-2-
carboxamide
509.4
84
0
4-( {2- [(4-bromophenyl) amino] -
qumazoim-o-yi/ oxy ^-in -i^z-
piperidin- 1 -ylethyl)pyridine-2-
carboxamide
548.5
85
0
H
4" ( {2- [(4-bromophenyl) amino] -
qmnazoiin-o-yi/oxy^-iN -propyi-
pyridine-2-carboxamide
479.3
86
0
H
4-( {2- [(4-bromophenyl) amino] -
quinazolin-6-yl} oxy)-N-[2-
(dimethylamino)ethyl]pyridine-2-
carboxamide
508.4
87
F
I
H
N-methyl-4- { [2-({ 3- [(trifluoro-
methyl)thio]phenyl} amino)-
quina2olin"6-yl]oxy } pyridine-2-
carboxamide
472.5
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Example
Structure
Name
MH+
88
o
F H
4-( {2- [(4-chloro-2-fluorophenyl)-
oiiiirio J cjumazoiiii-o-yi j oxy ^ in -
methylpyridine-2-carboxamide
424.8
89
GH3 0
IN IN
J
H
4-({2-[(4-chloro-3-methylphenyl)-
amino]quinazolin-6-yl} oxy)-N-
inciJiyipyriame-z-carDOxaiiuue
420.9
90
s
H
4-( { 2- [(4-butylphenyl)ainiiio] -
qumazolin-6-yl} oxy)-N-methyl-
P5Tidme-2-carboxainide
428.5
Example 91
Synthesis of (4-l2-[(4-bromo-3-methvlphenvl)ammo1(6-qumQlYlQxy))-
(2-DYridyn)-N-methvlcarbQxamide
H
Step 1 . Synthesis of 2-chloroquinolin-6-ol
A solution of quinoline2,6-diol (leq) in THF (0.25M) was treated v^ith POCI3
(1.1 eq) and a drop of DMF. Crushed ice was added to the reaction mixture and EtOAc
was added and neutralized with a solution of sodium bicarbonate. The mixture was
brought back to pH 6-7 with IN HCl and ethyl acetate layer was separated, washed with
water and brine to provide title compoimd.
MS: MH''= 180.6
Step 2. Synthesis of 2-r(4-bromo-3-methylphenyl)amino]Quinolin-6-ol
The mixture containing 2-chloroquinolin-6-ol (leq), 4-bromo3-methylaniline
(2eq) and diisopropylethylamine in ethanol (IM) was refluxed overnight. The resultant
mixture was concentrated and purified on silica gel to provide the desired product. The
mixture containing 2-cliloroquinolin-6-ol (leq), 4-bromo3-methylaniline (2eq) and
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diisopropylethylamine in ethanol (IM) was refluxed overnight. The resxiltant mixture
was concentrated and purified on silica gel to provide the desired product.
MS: MH^ = 329.1
Step 3 . Synthesis of (A-il-K 4-bromo-3 -methylphenvDaminol (6-quinolvloxv) > (2-
pyridyn)-N"methylcarboxamide
The mixture of 2-[(4-bromo-3-methylphenyl)amino]quinolin-6-ol and potassium
bis(trimethylsilyl)amide (2eq), was stirred in dimethylformamide for 30 min at room
temperature. To this mixture was added (4-cliloro(2-pyridyl)-N-methylcarboxamide
(leq) and potassium carbonate (1.2eq) and micro waved for 6 mins at 170 °C. The
reaction mixture was then concentrated and partitioned between ethyl acetate and water.
The organic layer was separated and washed with brine, dried, filtered and concentrated.
Purification on Prep LC yielded the desired product.
MS: MH^ =463.3
Example 92
Synthesis of N-methyl-4- \(2- 1 [3 -(1 -methylethynphenyl"| amino ) q uinolin-6-
yDoxy]pvridine-2"Carboxamide
Following the procedure of Example 91, N-methyl-4-[(2-{[3-(l-methyletliyI)-
phenyl] amino} quinolin-6-yl)oxy]pyridine-2-carboxamide was synthesized.
MS:MH'" =413,5
H
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Example 93
Synthesis of 4"r2-r3"tert-Butvl-phenvlamino)-quinoxalin-6-yloxv1-
PVridine-2-carboxylic acid methvlamide
1. Synthesis of (3-/err-Butyl-phenyl)-(6-methoxy-quinoxalin-2-yl)-amine
A solution containing 2-chloro-6-methoxyquinoxaline (synthesized as described
in J. Chem, Soc. Perkin Trans 2001, 978-984) (leq), 3-^butylaniHne (2eq) in ethanol was
heated at 80°C overnight. The resultant mixture was concentrated and partitioned
between ethyl acetate and water. The organic layer was washed with brine and dried.
Purification on silica gel gave the desired product.
MS: MH^ = 308.3
2. Synthesis of 2-(3-rer^Butyl-phenylamino)-quinoxalin-6-ol
The mixture of (3-^er^Butyl-phenyl)-(6-methoxy-quinoxalin-2-yl)-amine and
hydrobromic acid (48%) was subjected to the microwave at 140°C for 6 mins, to yield the
desired product. The mixture was neutralized with sodium bicarbonate solution and
taken in ethyl acetate. The organic layer was washed with water and brine, concentrated,
and purified on silica gel.
MS:MH^ =294.3
3 . Synthesis of 4- [2-(3 -f erf-Butyl-phenylamino)-quinoxalin-6-yloxy]-pyridine-2-
carboxylic acid methylamide
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The mixture containing 2-(3-/e7Y-butyl-phenylamino)-quinoxalin-6-ol (1 eq),
potassiumbis(trimethylsilyl)amide (4eq), was stirred in dimethylformamide for 30 min. at
room temperature. To this mixture was added 4-chloro-pyridine-2-carboxylic acid
methylamide (1 eq) and potassium carbonate (1.2 eq) and microwaved for 6 mins. at
5 170°C. The reaction mixture was then concentrated and partitioned between ethyl acetate
and water. The organic layer was separated and washed with brine^ dried, filtered and
concentrated. Purification on Prep LC yielded the desired product.
MS: MH^ = 428.5Example 94
Raf/Mek Filtration Assay
10 Buffers
Assay buffer: 50 mM Tris, pH 7.5, 15 mM MgCl2, 0.1 mM EDTA, 1 mM DTT
Wash buffer: 25 mM Hepes, pH 7.4, 50 mM sodium pyrophosphate, 500 mM
NaCl
Stop reagent: 30 mM EDTA
1 5 Materials
Raf, active:
Mek, inactive:
33p.ATP:
96 well assay plates:
20 Filter apparatus:
96 well filtration plates:
Scintillation fluid:
Assay conditions
Raf approximately 120 pM
25 Mek approximately 60 nM
33P-ATP 100 nM
Reaction time 45-60 minutes at room temperature
Assay protocol
Raf and Mek were combined at 2X final concentrations in assay buffer (50 mM
30 Tris, pH 7.5, 15 mM MgCl2. 0.1 mM EDTA and 1 mM DTT) and dispensed 15 |xl per
well in polypropylene assay plates (Falcon U-bottom polypropylene 96 well assay plates
-54-
Upstate Biotech #14-352
Upstate Biotech #14-205
NEN Perkin Elmer #NEG 602 h
Falcon U-bottom polypropylene plates #35-1 190
Millipore #MAVM 096 OR
Millipore Immobilon 1 #MAIP NOB
Wallac OptiPhase "SuperMix" #1200-439
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#35-1190. BackgroTind levels axe determined in wells containing Mek and DMSO
without Raf .
To the Raf/Mek containing wells was added 3 of 1 OX of a raf kinase inhibitor
test compound diluted in 100% DMSO. The raf kinase activity reaction was started by
5 the addition of 12 lul per well of 2.5X 33p.ATP diluted in assay buffer. After 45-60
minutes, the reactions were stopped with the addition of 70 jal of stop reagent (30 mM
EDTA). Filtration plates were pre-wetted for 5 min Avith 70% ethanol, and then rinsed by
fihration with wash buffer. Samples (90 \xl) from the reaction wells were then transferred
to the filtration plates. The filtration plates were washed 6X with wash buffer using
10 Millipore filtration apparatus. The plates were dried and 100 |ll1 per well of scintillation
fluid (Wallac OptiPhase "SuperMix" #1200-439) was added. The CPM is then
determined using a Wallac Microbeta 1450 reader.
Example 95
ASSAY 2: Biotinvlated Raf Screen
15 In Vitro Raf Screen
The activity of various isoforms of Raf serine/threonine kinases can be measured
by providing ATP, MEK substrate, and assaying the transfer of phosphate moiety to the
MEK residue. Recombinant isoforms of Raf w^ere obtained by purification from sf9
insect cells infected with a human Raf recombinant baculoviras expression vector.
20 Recombinant kinase inactive MEK was expressed in E. coli and labeled with Biotin post
purification. For each assay, test compounds were serially diluted in DMSO then mixed
with Raf (0.50 nM) and kinase inactive biotin-MEK (50 nM) in reaction buffer plus ATP
(1 |LiM). Reactions were subsequently incubated for 2 hours at room temperature and
stopped by the addition of 0.5 M EDTA. Stopped reaction mixture was transferred to a
25 neutradavin-coated plate (Pierce) and incubated for 1 hour. Phosphorylated product was
measured with the DELFIA time-resolved fluorescence system (Wallac), using a rabbit
anti-p-MEK (Cell Signaling) as tlae primary antibody and europium labeled atiti-rabbit as
the secondary antibody. Time resolved fluorescence was read on a Wallac 1232 DELFIA
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fluorometer. The concentration of each compound for 50% inhibition (IC50) was
calculated by non-linear regression using XL Fit data analysis software.
Using the procedures of Examples 94 or 95, the compounds of Examples 1-93
were shown to have a raf kinase inhibitory activity at an IC50 of less than 5 |j-M.
5 While the preferred embodiment of the invention has been illustrated and
described, it will be appreciated that various changes can be made therein without
departing firom the spirit and scope of the invention.
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The embodiments of the invention in which an exclusive property or privilege is
claimed are defined as follows:
1 . A compound of the formula (I):
R4 (I)
wherein, Xi and X2 are independently selected from N or CH, provided that at
least one of Xi and X2 is N;
Y is O, S, CH2, NR5, -N(R5)C(=0)- or ~C(-0)N(R5)-;
Z is ^2, NR6R7, NR5(C=0)R8, NR5(C-S)R8, or NR5-AA, wherein AA is a
substituted or unsubstituted amino acid and the dashed line represents a single or double
bond;
A] is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl,
polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl, lieteroaryl-
heteroaryl, cycloalkylalkyl, cycloalkylaryl, heterocycloalkyl, heterocycloalkylalkyl,
heterocycloaryl, arylalkyl, heteroarylalkyl, biarylalkyl, or heteroarylarylalkyl;
A2 is substituted or unsubstituted aryl or heteroaryl;
Rl is O or H, and R2 is NR6R7 or hydroxyl; or R^ is taken together with R2 to
form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the
dashed line represents a single or double bond;
R3 and R3t are independently selected from hydrogen, halogen, loweralkyl, or
loweralkoxy;
R4 is hydrogen, hydroxyl or substituted or unsubstituted alkyl;
R5 is hydrogen, -C(=0)(R5a)-, or substituted or xmsubstituted alkyl, alkoxyalkyl,
aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and
heteroarylalkyl, where R^^ is substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and
heteroarylalkyl;
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and R7 are independently selected jfrom hydrogen, and substituted or
imsubstituted alkyl, alkoxy, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5
and R7 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl;
and
Rg is substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, amino,
alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkyloxy,
cycloalkylamino, dicycloalkylamino, cycloalkyloxyalkyl, cycloalkylaminoalkyl,
dicycloalkylaminoalkyl, (alkyl)(cycloalkyl)aminoalkyl, heterocycloalkyl, hetero-
cycloalkyloxy, heterocycloalkylamino, diheterocycloalkylamino, heterocycloalkyl-
oxyalkyl, heterocyclo alkylaminoalkyl, (alkyl)(heterocycloalkyl)aminoalkyl,
diheterocycloalkylaminoalkyl, aryl, aryloxy, arylamino, diarylamino, aryloxyalkyl,
arylaminoalkyl, diarylaminoalkyl, (alkyI)(aryl)aminoalkyl, heteroaryl, heteroaryloxy,
heteroarylamino, diheteroarylamino, (alkyl)(heteroaryl)aminoalkyl, heteroaryloxyalkyl,
heteroarylaminoalkyl, diheteroarylaminoalkyl, (aryl)(heteroaryl)aminoalkyl or
a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
2. A compoiond of Claim 1 wherein X][ is N.
3 . A compound of Claim 1 wherein X2 is N.
4. A compound of Claim 1 wherein both and X2 are N.
5. A compound of Claim 1 wherein Y is O.
6. A compound of Claim 1 wherein Aj is selected from the group consisting
of substituted or unsubstituted phenyl, phenylalkyl, pyridyl, pyrimidinyl, pyridylalkyl,
pyrimidinylalkyl, alkylbenzoate, thiophene, thiophene-l-carboxylate, indenyl, 2,3-
dihydroindenyl, tetralinyl, triflourophenyl, (triflouromethyl)thiophenyl, morpholinyl, N-
piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-
dihydroindoljd, 1 -aceytl -2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2. l]hept-2-yl,
pyrrolidinyl, pyrrolidin- 1 -yl, pyrrolidin- 1 -ylalkyl, 4-amino(imino)methylphenyl,
isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl,
benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, napththalenyl,
benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl.
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phenylalkylsulfonyl, 9H-floiiren- 1 -yl, piperidin-l-yl, piperidin-l-ylalkyl, cyclopropyl,
cyclopropylalkyl, furanyl, N-methylpiperidin-4-yl5 pyrTolidm-4-ylpyridiiiyl5 4-diazepan-
1-yl, hydroxypyrrolidn- 1 -yl, dialkylaminopyrrolidin-l-yl, and l,4'-bipiperidin-r-yL
7. A compound of Claim 1 wherein Ai is substitxited or unsubstituted phenyl.
8. A compound of Claim 7 wherein Ai is substituted phenyl selected from
the group consisting of substituted or xmsubstituted hydroxyphenyl, hydroxyalkylphenyl,
alkylphenyl, dialkylphenyl, trialkylphenyl, alkoxyphenyl, dialkoxyphenyl,
alkoxyalkylphenyl, halophenyl, dihalophenyl, haloalkylphenyl, haloalkoxyphenyl^
alkylhalophenyl, alkoxyhalophenyl, alkylthiophenyl, aminophenyl, nitrophenyl,
acetylphenyl, sulfamoylphenyl, biphenyl, alkoxybiphenyl, cyclohexylphenyl,
phenyloxyphenyl, dialkylaminophenyl, morpholinylphenyl^ heterocyclylcarbonylphenyl,
heterocyclylphenyl, heterocyclylalkylphenyl, furanylphenyl, (1 ,4'-bipiperidin- 1
ylcarbonyl)phenyl, pyrimidin-5-ylphenyl, and quinolidinylphenyl.
9. A compound of Claim 8 wherein A^ is substituted phenyl selected from
the group consisting of chlorophenyl, flourophenyl, bromophenyl, iodophenyl,
dichlorophenyl, difluorophenyl, dibromophenyl, flurorchlorophenyl, bromochlorophenyl,
trifluoromethylphenyl, trifluoromethoxyphenyl, alkylbromophenyl, trifluoromethyl-
bromophenyl, alkylchlorophenyl, triflouromethylchlorophenyl, alkylflourophenyl, and
triflouromethylfluorophenyL
10. A compound of Claim 1 wherein A2 is substituted or unsubstituted
pyridyl.
C.
11. A compomd of Claim 1 wherein Z is ^2 and is O
Ri
12. A compound of Claim 1 wherein Z is ^^a, R2 is NR^Ry, R5 is
hydrogen and R7 is selected from hydrogen, and substituted or unsubstituted alkyl,
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alkoxy, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl,
heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl.
13. A compound of Claim 1 wherein Z is ^^2 and is taken together
with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group.
14. A compound of Claim 1 wherein R3 is loweralkoxy.
15. A compound of Claim 15 wherein R3 is metlioxy.
16. A compound of Claim 1 wherein R4 is hydrogen.
17. A compound of Claim 1 wherein R4 is loweralkyl.
18. A compoxmd of Claim 17 wherein R4 is methyl.
19. A compound of Claim 1 having the formula (V):
(V)
or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
20. A compovmd of claim 1 wherein Z is
is H, and R7 is methyl.
R2, Rj is O, R2 is NRgRy, Re
21. A compovmd of the formula (II) :
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wherein is N or CH;
Y is O, S, CH2. NR5, -N(R5)C(-0)- or ~C(=0)N(R5)s
Z is ^^2, NR6R7, NR5(C-0)R8, NR5(C=S)R8, or NR5-AA, wherein AA is a
substituted or unsubstituted amino acid and the dashed Une represents a single or double
bond;
A2 is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl,
polycycUc aryl, polycycUc arylalkyl, heteroaryl, biaryl, heteroarylaryU
heteroarylheteroaryl, cycloalkylalkyl, cycloalkylaryl, heterocycloalkyl,
heterocycloalkylalkyl, heterocycloaryl, arylalkyl, heteroarylalkyl, biarylalkyl, or
heteroarylarylalkyl;
A2 is substituted or unsubstituted aryl or heteroaryl;
Rl is O or and R2 is NR^Ry or hydroxyl; or Ri is taken together with R2 to
form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the
dashed line represents a single or double bond;
R3 and R3' are independently selected from hydrogen, halogen, loweralkyl, or
loweralkoxy;
R4 is hydrogen, hydroxyl or substituted or unsubstituted alkyl;
R5 is hydrogen, -C(=0)(R5a)-, or substituted or unsubstituted alkyl, alkoxyalkyl,
aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and
heteroarylaUcyl, where R5a is substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and
heteroarylalkyl ;
R5 and R7 are independently selected from hydrogen, and substituted or
unsubstituted alkyl, alkoxy, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5
and R7 are taken together to form substituted or imsubstituted heterocyclo or heteroaryl;
and
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Rg is substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, amino,
alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkyloxy,
cycloalkylamino, dicycloalkylamino, cycloalkyloxyalkyl, cycloalkylaminoalkyl,
dicycloalkylaminoalkyU (alkyl)(cycloalkyl)aminoalkyl5 heterocycloalkyl, hetero-
cycloalkyloxy, heterocycloalkylamino, diheterocycloalkylamino, heterocycloalkyl-
oxyalkyl, lieterocycloalkylaminoalkyl, (alkyl)(heterocycloalkyl)aminoalkyl,
diheterocycloalkylaminoalkyl, aryl, aryloxy, arylamino, diarylamino, aryloxyalkyl,
arylaminoalkyl, diarylaminoalkyl, (alkyl)(aryl)aminoalkyl, heteroaryl, heteroaryloxy,
heteroarylainino, diheteroarylamino, (alkyl)(heteroaryl)aminoalkyl, heteroaryloxyalkyl,
heteroarylaminoalkyl, diheteroarylaminoalkyl, (aryl)(heteroaryl)aminoalkyl or
a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
22. A compound of Claim 21 wherein is CH.
23 . A compound of Claim 21 wherein R4 is hydrogen.
24. A compoimd of Claim 21 wherein R4 is methyl.
25. A compoimd of Claim 21 wherein Aj is selected from the group consisting
of substituted or unsubstituted phenyl, pheaylalkyl, pyridyl, pyrimidinyl, pyridylalkyl,
pyrimidinylalkyl, alkylbenzoate, tliiophene, thiophene-2-carboxylate, indenyl, 2,3 -
dihydroindenyl, tetralinyl, triflourophenyl, (triflouromethyl)thiophenyl, morpholinyl, N-
piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-
dihydroindolyl, 1 -aceytl -2,3-dihydroindolyl, cycloheptyl, bicyclo[2,2. 1 ]hept-2-yl,
pyrrolidinyl, pyrrolidin- 1 -yl, pyrrolidin- 1 -ylalkyl, 4-amino(imino)methylphenyl,
isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl,
benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, napththalenyl,
benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl,
phenylalkylsulfonyl, 9H-flouren-l-yl, piperidin- 1 -yl, piperidin-1-ylalkyl, cyclopropyl,
cyclopropylalkyl, furanyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyU 4-diazepan-
1-yl, hydroxypyrrolidn-l-yl, dialkylaminopyrrolidin-l-yl, and l54'-bipiperidin-r-yl.
26. A compoimd of Claim 25 wherein A^ is substituted or unsubstituted
phenyl.
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27. A compovind of Claim 25 wherein is substituted phenyl selected from
the group consisting of substituted or imsubstituted hydroxyphenyl, hydroxyalkylphenyl,
alkylphenyl, dialkylphenyl, trialkylphenyl, alkoxyphenyl, dialkoxyphenyl,
allcoxyalkylphenyl, halophenyl, dihalophenyl, haloalkylphenyl, haloalkoxyphenyl,
alkylhalophenyl, alkoxyhalophenyl, alkylthiophenyl, aminophenyl, nitrophenyl,
acetylphenyl, sulfamoylphenyl, biphenyl, alkoxybiphenyl, cyclohexylphenyl,
phenyloxyphenyl, dialkylaminophenyl, morpholinylphenyl, heterocyclylcarbonylphenyl,
heterocyclylphenyl, heterocy clylalkylphenyl, furanylphenyl, ( 1 ,4'-bipiperidin- 1
ylcarbonyl)phenyl, pyrimidin-5-ylphenyl, and quinolidinylphenyl.
28. A compound of Claim 25 wherein A^ is substituted phenyl selected from
the group consisting of chlorophenyl, flourophenyl, bromophenyl, iodophenyl,
dichlorophenyl, difluorophenyl, dibromophenyl, flurorchlorophenyl, bromochlorophenyl,
trifluoromethylphenyl, trifluoromethoxyphenyl, alkylbromophenyl, trifluoromethyl-
bromophenyl, alkylchlorophenyl, trifloxH"omethylchlorophenyl, alkylflourophenyl, and
triflouromethylfluorophenyL
29. A compoxmd of Claim 21 wherein A2 is substituted or unsubstituted
pyridyl.
— c.
30. A compound of Claim 21 wherein Z is ^2 and Ri is O and the
dashed line represents a single or double bond.
31. A compound of Claim 21 wherein Z is ^2 and R2 is NR^Ry, Rg is
hydrogen and Ry is selected from hydrogen, and substituted or unsubstituted alkyl,
alkoxy, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl,
heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl.
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32. A compoimd of Claim 21 wherein Z is
and is taken together
with R2 to form a substituted or imsubstituted heterocycloalkyl or heteroaryl group.
33. A compound of Claim 21 wherein R3 is loweralkoxy.
34. A compound of Claim 33 wherein R3 is methoxy.
35. A compovmd of Claim 21 wherein R4 is hydrogen.
36. A compoxmd of Claim 21 wherein R4 is loweralkyl.
37. A compoimd of Claim 36 wherein R4 is methyl.
R
38. A compound of claim 21 wherein Z is
NR5R7, R5 is H, and R7 is methyl.
and Rj is R2 is
39. A compoimd of Claim 21 having the formula (VI):
(VI)
or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof
40. A compound of the formula (III):
(III)
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wherein X2 is N or CH;
Y is S, CH2, NR5, -N(R5)C(-0)- or -C(=0)N(R5)-;
Z is R2, NR6R7, NR5(C-0)R8, NR5(C=S)R8, or NR5-AA, wherein AA is a
substituted or unsubstituted amino acid and the dashed Une represents a single or double
bond;
Ai is substituted or unsubstituted alkyl, cycloalkyi, heterocycloalkyl, aryl,
polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl.
heterocycloalkylalkyl, heterocycloaryl, arylalkyl, heteroarylalkyl, biarylalkyl, or
heteroarylarylalkyl;
A2 is substituted or xmsubstituted aryl or heteroaryl;
Rl is O or H, and R2 is NR5R7 or hydroxyl; or Rj is taken together with R2 to
form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the
dashed line represents a single or double bond;
R3 and R3r are independently selected from hydrogen, halogen, loweralkyl, or
loweralkoxy;
R4 is hydrogen, hydroxyl or substituted or unsubstituted alkyl;
R5 is hydrogen, -C(=0)(R5^-, or substituted or unsubstituted alkyl, alkoxyalkyl,
aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and
heteroarylalkyl, where is substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and
heteroarylalkyl;
R5 and R7 are independently selected from hydrogen, and substituted or
unsubstituted alkyl, alkoxy, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5
and Ry are taken together to form substituted or unsubstituted heterocyclo or heteroaryl;
and
Rg is substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, amino,
alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkyloxy,
cycloalkylamino, dicycloalkylamino, cycloalkyloxyalkyl, cycloalkylaminoalkyl,
dicycloalkylaminoalkyl, (alkyl)(cycloalkyl)aminoalkyl, heterocycloalkyl, hetero-
heteroarylheteroaryl,
cycloalkylalkyl,
cycloalkylaryl,
heterocycloalkyl.
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cycloalkyloxy, heterocycloalkylamino, diheterocycloalkylamino, heterocycloalkyl-
oxyalkyl, heterocycloalkylaminoalkyl, (alkyl)(heterocycloalkyl)aminoalkyl,
diheterocycloalkylaminoalkyl, aryl, aryloxy, arylainino, diarylamino, aryloxyalkyl,
arylaminoalkyl, diarylaminoalkyl, (alkyl)(aryl) amino alkyl, heteroaryl, heteroaryloxy,
heteroarylamino, diheteroarylamino, (alkyl)(heteroajtyl)aminoalkyl, heteroaryloxyalkyl,
heteroarylaminoalkyl, diheteroarylaminoalkyl, (aryl)(heteroaryl)ammoalkyl or
a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
41 . A compound of Claim 40 wherein X2 is CH.
42. A compound of Claim 40 wherein R4 is hydrogen.
43. A compound of Claim 40 wherein R4 is methyl.
44. A compovind of Claim 40 wherein A^ is selected from the group consisting
of substituted or unsubstituted phenyl, phenylalkyl, pyridyl, pyrimidinyl, pyridylalkyl,
pyrimidinylalkyl, alkylbenzoate, thiophene^ thiophene-2-carboxylate, indenyl, 2,3-
dihydroindenylj tetralinyl, trifloxirophenyl, (triflouTomethyl)thiophenyl, morpholinyl, N-
piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-
dihydroindolyl, l-ace3^1-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2. l]hept-2-yl,
pyrrolidinyl, pyrrolidin- 1 -yl, pyrrolidin- 1 -ylalkyl, 4-amino(imino)methylphenyl5
isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl,
benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, napththalenyl,
benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl,
phenylalkylsulfonyl, 9H-fIouren- 1 -yl, piperidin-l-yl, piperidin-l-ylalkyl, cyclopropyl,
cyclopropylalkyl, furanyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-
1-yl, hydroxypyrrolidn- 1 -yl, dialkylaminopyrrolidin-l-yl, and l54'-bipiperidin-r-yl.
45. A compoxmd of Claim 44 wherein A^ is substituted or unsubstituted
phenyl.
46. A compound of Claim 44 wherein A;^ is substituted phenyl selected from
the group consisting of substituted or unsubstituted hydroxyphenyl, hydroxyalkylphenyl,
alkylphenyl, dialkylphenyl, trialkylphenyl, alkoxyphenyl, dialkoxyphenyl.
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alkoxyalkylphenyl, halophenyl, dihalophenyl, haloalkylphenyl, haloalkoxyphenyl,
alkylhalophenyl, alkoxyhalophenyl, alkylthiophenyl, aminophenyl, iiitxophenyl,
acetylphenyl, sulfamoylphenyl, biphenyl, alkoxybiphenyl, cyclohexylphenyl,
phenyloxyphenyl, dialkylaminophenyl, morpholinylphenyl, heterocyclylcarbonylphenyl,
heterocyclylphenyl, heterocyclylalkylphenyl, fliranylphenyl, ( 1 ,4'-bipiperidin- 1 -
ylcarbonyl)phenyU pj^imidin-S-ylphenyl, and quinolidinylphenyl.
47. A compound of Claim 44 wherein is substituted phenyl selected from
the group consisting of chlorophenyl, flourophenyl, bromophenyl, iodophenyU
dichlorophenyl, difluorophenyU dibromophenyl, flxororchlorophenyl, bromochlorophenyl,
trifluoromethylphenyl, trifluoromethoxyphenyl, alkylbromophenyl, trifluoromethyl-
bromophenyl, alkylchlorophenyl, triflouromethylchlorophenyl, alkylflourophenyl, and
triflouromethy Ifluoropheny 1 .
48. A compound of Claim 40 wherein A2 is substituted or unsubstituted
pyridyl.
C
49. A compoxmd of Claim 40 wherein Z is ^^2 and is O and the
dashed line represents a single or double bond.
50. A compound of Claim 40 wherein Z is and R2 is NR^Ry, R5 is
hydrogen and R7 is selected from hydrogen, and substituted or unsubstituted alkyl,
alkoxy, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl,
heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl.
51. A compomd of Claim 40 wherein Z is ^2 and Rj is taken together
with R2 to form a substituted or vinsubstituted heterocycloalkyl or heteroaryl group.
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52. A compound of Claim 40 wherein R3 is loweralkoxy.
53. A compoimd of Claim 52 wherein R3 is methoxy.
54. A compound of Claim 40 wherein R4 is hydrogen.
55. A compovmd of Claim 40 wherein R4 is loweralkyl.
56. A compound of Claim 55 wherein R4 is methyl.
57. A compound of claim 40 wherein Z is
Rg is H, and R7 is methyl.
R2, Rl is O, R2 is NR6R7:
58. A compound of Claim 40 having the formula (VII) :
(VII)
or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
59. A compound of the formula (IV):
(IV)
wherein Y is O, S, CH2, NHR5, -N(R5)C(=0)- or -C(=0)N(R5)-;
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^2, NR6R7, NR5(C=0)R8, NR5(C=S)R8, or NR5-AA, wherein AA is a
Z IS
substituted or unsubstituted amino acid and the dashed Une represents a single or double
bond;
Ai is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl,
polycyclic aryl, polycyclic arylalkyl, heteroaryl, biaryl, heteroarylaryl^
heterocycloalkylalkyl, heterocycloaryl, arylalkyl, heteroarylalkyl, biarylalkyl, or
heter o aryl ary lalky 1 ;
A2 is substituted or unsubstituted aryl or heteroaryl;
Rl is O or H, and R2 is NR5R7 or hydroxyl; or Rj is taken together with R2 to
form a substituted or unsubstituted heterocycloalkyl or heteroaryl group; wherein, the
dashed line represents a single or double bond;
R3 and R3. are independently selected from hydrogen, halogen, loweralkyl, or
loweralkoxy;
R4 is hydrogen, hydroxyl or substituted or unsubstituted alkyl;
R5 is hydrogen, ~C(^0)(R^^', or substituted or unsubstituted alkyl, alkoxyalkyl,
aminoalkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and
heteroarylalkyl, where R^^ is substituted or unsubstituted alkyl, alkoxyalkyl, aminoalkyl,
cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and
heteroarylalkyl;
R5 and R7 are independently selected from hydrogen, and substituted or
unsubstituted alkyl, alkoxy, alkoxyalkyl, aminoalkyl, amidoalkyl, acyl, cycloalkyl,
heterocycloalkyl, aryl, heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl; or R5
and R7 are taken together to form substituted or unsubstituted heterocyclo or heteroaryl;
and
Rg is substituted or unsubstituted alkyl, alkenyl, alkynyl, alkoxy, amino,
alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, cycloalkyl, cycloalkyloxy,
cycloalkylamino, dicycloalkylamino, cycloalkyloxyalkyl, cycloalkylaminoalkyl,
dicycloalkylaminoalkyl, (alkyl)(cycloalkyl)aminoalkyl, heterocycloalkyl, hetero-
cycloallcyloxy, heterocycloalkylamino, diheterocycloalkylamino, heterocycloalkyl-
oxyalkyl, heterocycloalkylaminoalkyl, (alkyl)(heterocycloalkyl)aminoalkyl.
heteroarylhetero aryl.
cycloalkylalkyl,
cycloalkylaryl.
heterocycloalkyl.
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PCT/US2004/034185
diheterocycloalkylaminoalkyl, axyl, axyloxy, arylaniino, diarylatnino, aryloxyalkyl,
arylaminoalkyl, diarylatninoalkyl, (alkyl)(axyl)am.inoalkyl, heteroaryl, heteroaryloxy,
heteroarylamino, diheteroarylamino, (alkyl)(heteroaryl)aminoalkyl, heteroaryloxyalkyl,
heteroarylaminoalkyl, diheteroarylaminoalkyl, (aryl)(heteroat:yl)atninoalkyl or
a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
60. A compound of Claim 59 wherein R4 is hydrogen.
61. A compound of Claim 59 wherein R4 is methyl.
62. A compound of Claim 59 wherein Y is O.
63. A compound of Claim 59 wherein A^ is selected from tlie group consisting
of substituted or unsubstituted phenyl, phenylalkyl, pyridyl, pyrimidinyl, pyridylalkyl,
pyrimidinylalkyl, alkylbenzoate, thiophene, thiophene-2-carboxylate5 indenyl, 2,3-
dihydroindenyl, tetralinyl, triflourophenyl, (triflouromethyl)thiophenyl5 morpholinyl, N-
piperazinyl, N-morpholinylalkyl, piperazinylalkyl, cyclohexylalkyl, indolyl, 2,3-
dihydroindolyl, 1 -aceytl-2,3-dihydroindolyl, cycloheptyl, bicyclo[2.2. l]hept-2-yl,
pyrrolidinyl, pyrrolidin- 1 -yl, pyrrolidin- 1 -ylalkyl, 4-amino(imino)methylphenyl,
isoxazolyl, indazolyl, adamantyl, bicyclohexyl, quinuclidinyl, imidazolyl,
benzimidazolyl, imidazolylphenyl, phenylimidazolyl, pthalamido, napthyl, napththalenyl,
benzophenone, anilinyl, anisolyl, quinolinyl, quinolinonyl, phenylsulfonyl,
phenylalkylsulfonyl, 9H-floiaren- 1 -yl, piperidin- 1 -yl, piperidin- 1 -ylalkyl, cyclopropyl,
cyclopropylalkyl, furanyl, N-methylpiperidin-4-yl, pyrrolidin-4-ylpyridinyl, 4-diazepan-
l-yl, hydroxypyrrolidu-l-yl, dialkylaminopyrrolidin- 1 -yl, and 1,4 -bipiperidin-l'-yL
64. A compound of Claim 63 wherein A^ is substituted or unsubstituted
phenyl.
65. A compound of Claim 63 wherein A^ is substituted phenyl selected from
the group consisting of substituted or unsubstituted hydroxyphenyl, hydroxyalkylphenyl,
alkylphenyl, dialkylphenyl, trialkylphenyl, alkoxyphenyl, dialkoxyphenyl,
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PCT/US2004/034185
alkoxyalkylphenyl, halophenyl, dihalophenyl, haloalkylphen}^, haloalkoxyphenyl,
alkylhalophenyl, alkoxyhalophenyl, alkylthiophenyl^ aminophenyl, nitrophenyl,
acetylphenyl, sulfamoylphenyl, biphenyl, alkoxybiphenyl, cyclohexylphenyl,
phenyloxyphenyl, dialkylaminophenyl, morpholinylphenyl, heterocyclylcarbonylphenyl,
heterocy clylphenyU heterocyclylalkylphenyl, furanylphenyl, ( 1 54'-bipiperidin- 1
ylcarbonyl)phenyl, pyrimidin-S-ylphenyl, and quinolidinylphenyl.
66. A compovmd of Claim 63 wherein is substituted phenyl selected from
the group consisting of chlorophenyl, flourophenyl, bromophenyl, iodophenyl,
dichlorophenyl, difluorophenyl, dibromophenyl, flurorchlorophenyl, bromochlorophenyl,
trifluoromethylphenyl, trifluoromethoxyphenyl, alkylbromophenyl, trifluoromethyl-
bromophenyl, alkylchlorophenyl, triflouromethylchlorophenyl, alkylflourophenyl, and
triflouromethylfluorophenyl.
67. A compound of Claim 59 wherein A2 is substituted or unsubstituted
pyridyl.
68. A compound of Claim 59 wherein Z is 1^2 and Rj is O
69. A compomd of Claim 59 wherein Z is ^2, R2 is NR5R75 Rg is
hydrogen and R7 is selected from hydrogen, and substituted or xxnsubstituted alkyl,
alkoxy, alkoxyalkyl, aminoalkyl, atnidoalkyl, acyl, cycloalkyl, heterocycloalkyl, aryl,
heteroaryl, alkyloxyalkylheterocyclo, and heteroarylalkyl.
70. A compound of Claim 59 wherein Z is ^2 and Rj is taken together
with R2 to form a substituted or unsubstituted heterocycloalkyl or heteroaryl group.
<
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^2, Rj is O, R2 is NR5R7,
71.
A compouad of claim 59 wherein Z is
R5 is H, and Ry is methyl.
72. A compoimd of Claim 59 wherein R3 is loweralkoxy.
73. A compound of Claim 72 wherein R3 is methoxy.
74. A compoimd of Claim 59 wherein R4 is hydrogen.
75. A compound of Claim 59 wherein R4 is loweralkyL
76. A compound of Claim 75 wherein R4 is methyl.
77. A compoimd of Claim 59 having the formula (VIII):
or a stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.
78. A composition comprising an amount of a compound of claims 1, 21, 30,
or 59 effective to inhibit Raf activity in a human or animal subject when administered
thereto, together with a pharmaceutically acceptable carrier.
79. A composition of Claim 78 which further comprises at least one additional
agent for the treatment of cancer.
80. A composition of Claim 79 in which the at least one additional agent for
the treatment of cancer is selected from irinotecan, topotecan, gemcitabine, 5-
fluorouracil, leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide,
(VIII)
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vinca alkaloids, imatinib, anthracyclines, rituximab, trastuzumab, dacarbazine,
aldesleukin, capecitabine, and Iressa (gefitinib).
81. A method of inliibiting Raf kinase activity in a himian or animal subject,
comprising administering to the human or animal subject a composition comprising an
amount of a compound of claims 1, 21, 40, or 59.effective to inhibit Raf kinase activity in
the human or animal subject.
82. A method for treating a cancer disorder in a human or animal subject,
comprising administering to the human or animal subject a composition comprising an
amount of a compound of claims 1, 21, 40, or 59 effective to inhibit Raf kinase activity in
the hmnan or animal subject.
83. A method of claim 82 which further comprises administering to the human
or animal subject at least one additional agent for the treatment of cancer.
84. A method of claim 82 in which the at least one additional agent for the
treatment of cancer is selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil,
leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca
alkaloids, imatinib, anthracyclines, rituximab, trastu2ximab, dacarbazine, aldesleukin,
capecitabine, and Iressa (gefitinib).
85. A method for treating a hormone dependent cancer disorder in a hxaman or
animal subject, comprising administering to the human or animal subject a composition
comprising an amoxmt of a compound of claims 1, 21, 40, or 59 effective to inhibit Raf
kinase activity in the human or animal subject.
86. A method of claim 85 wherein the hormone dependent cancer is breast
cancer or prostate cancer.
87. A method of claim 85 which further comprises administering to the human
or animal subject at least one additional agent for the treatment of cancer.
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88. A method of claim 87 in which the at least one additional agent for tlie
treatment of cancer is selected from irinotecan, topotecan, gemcitabine, 5-fluorouracil,
leucovorin carboplatin, cisplatin, taxanes, tezacitabinCj, cyclophosphamide^ vinca
alkaloids, imatinibj anthracyclines, rituximab, trastuzumab, dacarbazine, aldesleukin,
capecitabine, and Iressa (gefitinib).
89. A method for treating a hematological cancer disorder in a human or
animal subject, comprising administering to the human or animal subject a composition
comprising an amount of a compound of claims 1,21, 40, or 59 effective to inhibit Raf
kinase activity in the human or animal subject.
90. A method of claim 89 which further comprises administering to the human
or animal subject at least one additional agent for the treatment of cancer.
91. A method of claim 90 in which the at least one additional agent for the
treatment of cancer is selected from irinotecan, topotecan, gemcitabine, S-fluorouracil,
leucovorin carboplatin, cisplatin, taxanes, tezacitabine, cyclophosphamide, vinca
alkaloids, imatinib, anthracyclines, rituximab, trastuzumab, dacarbazine, aldesleukin,
capecitabine, and Iressa (gefitinib).
92. A compound of claims 1,21, 40, or 59 for use iii the treatment of cancer.
93. Use of a compound of claims 1, 21, 40, or 59 in the manufactxire of a
medicament for the treatment of cancer.
-74-
INTERNATIONAL SEARCH REPORT
[nf
nal Application No
PCT/US2004/034185
A. CLASSIFICATION OF SUBJECT MATTER
IPC 7 A61K31/517 A61K31/4709 C07D401/12
C07D401/14 A61P43/00
According to International Patent Cfassification (IPC) or to both national classification and tPC
B. FIELDS SEARCHED
Minimum documentation searched (classification system toliowed by ciasslficatlon symbols)
IPC 7 A61K C07D A61P
Documentation searciied otiier than minimum documentation to ttie extent that such documents al ^lud^ ^^^eiie\ds searched
r
Electronic data base consulted during the international search (name of data base and, where practical, search terms used)
EPO-Internal, WPI Data, BEILSTEIN Data, CHEM ABS Data
C. DOCUMENTS CONSIDERED TO BE RELEVANT
Category
Gftatfon of document, with indication, where appropriate, of the relevant passages
Relevant to claim No.
X
wo 03/024448 A2 (METHYLGENE INC(US))
27 March 2003 (2003-03-27)
page 68, paragraph 149
page 68, paragraph 151
page 103, paragraph 208; example 53;
compound 87
page 314; c1 aim 94
EP 1 072 263 Al (JAPAN TOBACCO INC (OP))
31 January 2001 (2001-01-31)
page 72; example 126
1-93
1-77
X
US 3 177 218 A (MONSANTO CHEM LTD (US))
6 April 1965 (1965-04-06)
column 1, formulae
examples
1-77
_/—
Further documents are listed In the continuation of box C.
ID
Patent family members are listed in annex.
° Special categories of cited documents :
"A" document defining the general state of the art which Is not
considered to be of particular relevance
■E' earlier document but published on or after the international
filing dale
"L" document which may throw doubts on priority claim(s) or
which is cited to establish the ptibltcatfon date of another
citation or other special reason (as specified)
'O' document referring to an oral disclosure, use, exhibition or
other means
■p' document published prior to the international filing date but
later than the priority date claimed
later document published after the fnternatlonal filing date
or priority date and not In conflict with the application but
cited to understand the principle or theory underlying the
invention
document of particular relevance; the claimed invention
cannot be considered novel or cannot be considered to
involve an inventive step when the document is tai?en alone
' Y" document of particular relevance; the claimed invention
cannot be considered to involve an inventive step when the
document is combined with one or more other such docu-
ments, such combination being obvious to a person skilled
in the art.
'&■ document member of the same patent family
Date of the actual completion of the international search
31 January 2005
Name and mailing address of the ISA
European Patent Office, P.B, 5818 Patentlaan 2
NL - 2280 HV Rijswijk
Tel. (+31-70) 340-2040, Tx. 31 651 epo nl,
Fax: (+31-70) 340-3016
Date of mailing of the international search report
17/02/2005
Authorized officer
Cortes, J
Form PCT/iSA/210 (second sheet) (January 2004)
INTERNATIONAL SEARCH REPORT
)nt nal Application No
Pi,i/uS2004/034185
C.(Continuation) DOCUMENTS CONSfDEREDTO BE RELEVANT
Category "
Citation of document, with indication, where appropriate, of the relevant passages
Relevant to cfaim No.
X
US 3 149 113 A (MONSANTO CHEM LTD (US))
15 September 1964 (1964-09-15)
examples
1-77
X
EP 0 096 214 Al (THE WELLCOME FOUNDATION
LIMITED (UK))
21 December 1983 (1983-12-21)
page 40 - page 44; example 24
page 76 - page 77; claim 12
1-77
X
DAVIS ET AL:
" 2 , 4-Di ami no-5-benzyl pyr i mi di nes and
Analogues as Antibacterial Agents. 11.
Quinolylmethyl Analogues with Basic
Substituents Conveying Specificity"
J. MED. CHEM.,
vol, 32, 1989, pages 1936-1942,
XP002315428
page 1936, formula 2
page 1937; compounds 36, 38, 39
1-77
X
DATABASE BEILSTEIN
27 June 1988 (1988-06-27),
XP002315429
Database accession no. BRN: 306344
Chemical Name:
bi s-(2-dimethylamino-'6!quinolyl )-methane
abstract
& SHIMIZU ET AL: YAKUGAKU ZASSHI,
vol. 64, no. 10, 1944, page 47,
1-77
X
DATABASE BEILSTEIN
26 February 1991 (1991-02-26),
XP002315430
Database accession no. BRN: 3888321
Chemical Name:
bi s-(2-di methyl ami no- ' 6 ! qui nolyl )-methane ;
pi crate
abstract
& SHIMIZU ET AL: YAKUGAKU ZASSHI,
vol. 64, no. 10, 1944, page 47,
1-77
A
WO 02/085857 A2 (BAYER CO (US))
31 October 2002 (2002-10-31)
page 1, paragraph 1
page 2, paragraph 1
page 47 - page 51
claim 27
1-93
A
WO 02/36570 Al (ASTRAZENECA UK LIMITED
(GB)) 10 May 2002 (2002-05-10)
page 1, paragraph 1
page 127 - page 128
claim 1
-/--
1-93
Form PCT/lSA/210 (continuation of second sheet] (January 2004)
INTERNATIONAL SEARCH REPORT .al Application No
P^,/ w^2004/034185
C.(Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT
Category °
Citation of document, with indication, wiiere appropriate, of the relevant passages
Relevant to clainn No.
P,X
DATABASE CHEMCATS
25 April 2003 (2003-04-25),
CHEMDIV, INC. PRODUCT LIBRARY:
XP000231519
Database accession no. 2001: 1976804
CHEMCATS
Chemical Name (CN):
Benzamide,
N-'2-( diethyl ami no )-4-methyl-6-quinol inyl !
-3-(dimethyl amlno)-
CAS Registry No. (RN): 685884-36-0
abstract
list of 9 compounds published in CHEMCATS
on 25-04-2003
1-20,
40-58
Form PCT/ISA/210 (coniinuallon of second sheet) (January 2004)
INTERNATIONAL SEARCH REPORT
iationa) application No.
PCT/US2004/034185
Box II Obser\Aations where certain claims were found unsearchable (Continuation of Item 2 of first sheet)
This International Search Report has not been established in respect of certain cfaims under Article 17(2)(a) for the follov/ing reasons:
1.
□
Claims Nos.:
because they relate to subject matter not required to be searched by this Authority, nameiy:
Although claims 81-91 are directed to a method of treatment of
the human/animal body, the search has been carried out and based on the
alleged effects of the compound/composition.
Claims Nos.:
because they relate to parts of the International Application that do not comply with tine prescribed requirements to such
an extent that no meaningful International Search can be carried out, specifically:
Claims Nos.:
because they ar© dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).
Box III Observations where unity of invention is lacking (Continuation of item 3 of first sheet)
This International Searching Authority found multiple inventions In this international application, as follows:
1 . I I As all required additional search fees were tinnely paid by the applicant, this International Search Report covers all
' — ' searchable claims.
2.
As ail searchable claims could be searched without effort justifying an additional fee, this Authority did not invite payment
of any additional fee.
3. I I As only some of the required additional search fees were timely paid by the applicant, this International Search Report
1 — ' covers only those claims for which fees were paid, specifically claims Nos.:
4.
No required additional search fees were timely paid by the applicant. Consequently, this International Search Report is
restricted to the invention first mentioned in the claimsj it is covered by claims Nos.:
Remark on Protest [ | The additional search fees were accompanied by the applicant's protest.
j I No protest accompanied the payment of additional search fees.
Form PCTyiSAy210 (continuation of first sheet (2)) (January 2004)
INTERNATIONAL SEARCH REPORT
\nU 3nal Application No
PCI/US2004/034185
Patent document
Publication
Patent family
Publication
cftea in search report
date
member(s)
date
wo 03024448 A2
27-03-2003
BR
0212510
A
24-08-2004
CA
2465978
Al
27-03-2003
EP
1429765
A2
2'^-n6-?nn4
US
2004106599
Al
/I X
wo \J \J Vj VJ "T
US
2004142953
Al
f \ X
EP 1072263 Al
AU
754716
B2
21-1 1-pnn?
AU
2855899
A
1 0_1 f)_1 QQQ
U l\
9909666
A
XX \J ^ €-\J\J 1.
CA
2325538
Al
30-09-1999
FT
20002103
A
17-1 1-2000
X/ XX £_Wwv
HU
0101275
A2
28-09-2001
NO
20004778
A
27-11-2000
HI
507760
A
25-10-2002
SK
14272000
A3
10-05-2001
Xw U ^ WW X
US
6410561
Bl
U X
25-06-2002
CN
1301154
X W X X ~
T
1
27-06-2001
ID
26099
A
23-11-2000
JP
3013989
B2
28-02-2000
JP
11335355
A
07-12-lQQQ
wo
9948492
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20-04-2003
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20-03-2003
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23-08-2001
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06-04-1965
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20-05-1986
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24-12-1984
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06-05-1986
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31-10-2002
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Form l=CT/ISA/210 (patent family annex) {January 2004)
INTERNATIONAL SEARCH REPORT
tr stional application No.
PCT/US2 004/034185
Box No. IV Text of the abstract (Continuation of item 5 of the first sheet)
New substituted quinazoline, q[uinoxaliner guinoline and isocfuinoline compounds
of formulae CD - (IV) , compositions and methods of inhibition of Raf kinase
activity in a h\iinan or animal subject are provided. The new compounds
compositions may be used either alone or in combination with at least one
additional agent for the treatment of a Raf kinase mediated disorder, such, as
cancer. The STobsti tuents are defined in the claims _
Form PCT/ISA/210 (continuation of first sheet (3)) (January 2004)
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